Quinolizinones as integrin inhibitors

ABSTRACT

The present invention is directed towards novel compounds that are effective inhibitors of integrins, particularly alphaIIbbeta3 or alphav integrins such as alphavbeta3 and alphavbeta5. One embodiment of the present invention comprises a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt, solvate, or metabolic precursor thereof. R1, R2, R3, and R4 are defined herein.

This application claims benefit of U.S. Provisional Application Ser. No.60/101,257, filed Sep. 21, 1998.

FIELD OF THE INVENTION

The present invention relates to compounds that inhibit certainintegrins, particularly to compounds that inhibit α_(v)β₃ and α_(IIb)β₃integrins, their synthesis and their use as integrin inhibitors.

BACKGROUND OF THE INVENTION

Integrins are a family of cell adhesion receptors. The integrin familyof proteins are expressed on the surface of a cell and contain a bindingsite that binds the cell to certain glycoproteins and therefore mediatecell-cell and cell-extracellular matrix (ECM)interactions.

They are heterodimer transmembrane proteins that consist of an alphaunit and a beta unit. The integrin family has been designated a standardnomenclature system based upon the structure of the alpha unit and thebeta unit of the receptor. Therefore, all compounds that have thedesignation α_(v) each share the same alpha unit. All compounds thathave the β₃ designation have the same beta subunit. The variouscombinations of those subunits give a wide array of heterodimers withdistinct cellular and adhesive specificities.

The family includes cell adhesion receptors such as α_(IIb)β₃(previously called GpIIb/IIIa, generally known as the fibrinogenreceptor), α_(v)β₃ (generally known as the vitronectin receptor), andα_(vβ) ₅ (generally known as the osteopontin receptor)

Some integrins (including α_(IIb)β₃, α_(v)β₃ and α_(v)β₅) bind to agroup of glycoproteins that contain the tripeptide moiety, Arg-Gly-Asp(RGD). While several members of the integrin family members may bind toRGD containing proteins, the physical configuration of the binding siteon each protein affects binding affinity between the integrin and theRGD containing glycoprotein. Nonetheless, each integrin may be capableof binding to more than one molecule containing the RGD moiety withdiffering degrees of effectiveness.

The integrin, α_(v)β₃, is a particularly important integrin familymember that has a wide range of reactivity. It is expressed on a varietyof cells, including endothelial cells, osteoclasts, platelets, andsmooth muscle cells, and binds to vitronectin and plays an importantrole in bone resporption, angiogenesis, and neovascularization. Thebinding of α_(v)β₃ to vitronectin is an important step in the process ofangiogenesis or neovascularization.

Angiogenesis is described as the formation of new blood vessels into atissue. Angiogenesis is an important process in neonatal growth, but isalso important in wound healing and in.the pathogenesis of a largevariety of clinically important diseases including tissue inflammation,arthritis, psoriasis, cancer, diabetic retinopathy, macular degenerationand other neovascular eye diseases. These clinical entities associatedwith angiogenesis are referred to as angiogenic diseases. See Folkman etal., Science, 235:442-447 (1987) and Folkman et al., J. B. C., 267:10931-10934 (1992).

It has been postulated that the growth of tumors depends on an adequateblood supply, which in turn is dependent on the growth of new vesselsinto the tumor; thus inhibition of angiogenesis can cause tumorregression in animal models. Integrin antagonists, such as αvβ3antagonists which inhibit angiogenesis are therefore useful in thetreatment of cancer for inhibiting tumor growth.

Inhibiting angiogenesis will slow or halt the growth of tumors.Inhibition of α_(v)β₃ is believed to cause tumor regression and induceapoptosis. The α_(v)β₃ integrin also binds to bone matrix proteins thatcontain the RGD moiety such as osteopontin, bone sialoprotein andthrombospondin. Inhibition of α_(v)β₃ is believed to have potentialtherapeutic value in the prevention of osteoporosis. α_(v)β₃ isimplicated in bone resorption at the level of osteoclasts and inosteoporosis such as described in WO 98/31359, WO 98/08840 and WO98/18461.

The binding of integrins such as α_(v)β₃, α_(v)β₁ and α_(v)β₅ tofibronectin has been linked to the specific internalization of Neisseriagonorrhoeae bacteria into epithelial cells. Additionally, the binding ofRGD containing domain of exogenous HIV-1 Tat protein is believed todecrease the function of dendric cells, possibly impairing antigenpresentation.

The integrin, α_(v)β₅, known primarily as the osteopontin receptor bindsto other RGD containing molecules including vitronectin. Inhibitors ofα_(v)β₅ have potential therapeutic value in the treatment inosteoporosis and angiogenesis.

Because of the similarity of molecules in the integrin family, integrinsexhibit a considerable degree of cross reactivity as is illustratedabove with the discussion regarding the α_(v)β₃ and α_(v)β₅ integrins.However, the inhibition of α_(v)β₃ and α_(v)β₅ or other integrins arerather unpredictable. One effective inhibitor of α_(v)β₃ may be alsoeffective inhibitor of α_(IIb)β₃ but not of α_(vβ) ₅. Other inhibitorsmay selectively inhibit one integrin but not inhibit other integrins.The use of a compound for a particular application may depend upon whichintegrins it inhibits and to what extent it inhibits other molecules.

There have been several publications which disclose potential inhibitorsof α_(v)β₃. Some of these publications include Haubner et al.,“Structural and Functional Aspects of RGD-Containing CyclicPentapeptides as Highly Potent and Selective Integrin α_(v)β₃Antagonists,” J. Am. Chem. Soc., Vol. 118, 7461-7472 (1996); Wong etal., “Studies on α_(v)b₃/Ligand Interactions Using a [³H] SK&F-107260Binding Assay,” Molec. Pharm, Vol. 50, pp. 529-537, (1996); Brooks,“Integrin α_(v)b₃: A Therapeutic Target,” DN&P Vol. 8(10), pp. 456-460(1997); Samanen et al., “Vascular Indications for Integrin αvAntagonists,” Current Pharmaceutical Design, Vol. 3, pp. 545-584 (1997);PCT Pub. No. WO 97/24124 to Smithkline Beecham Corporation ; PCT WO98/23608 to The Du Pont Merck Pharmaceutical Co; PCT WO 97/36862 to G.D. Searle & Co; PCT WO 97/36859 so G. D. Searle.

There are other publications which disclose inhibitors of otherintegrins. Some of these publications include PCT Pub. No. WO 94/08577to Merck & Co.; U.S. Pat. No. 5,084,466 to Alig et al.; PCT Publ. No. WO97/01540 to Smithkline Beecham Corporation; Kunicki et al., “Exchange ofArg-Gly-Asp (RGD) and Arg-Tyr-Asp (RYD) Binding Sequences in aRecombinant Murine Fab Fragment” J. Bio. Chem, Vol. 270, No. 28, pp.16660-16665 (1995); PCT Publ. No. WO 98/05774 to Merck & Co. Inc; U.S.Pat. No. 5,227,490 to Hartman et al.; U.S. Pat. No. 5,082,942 toMahuzier; PCT WO 97/26250 to Merck & Co.

However, despite all of the studies on integrin receptor antagonists,there is still a need for compounds that bind to particular integrinseffectively and particularly can effectively bind to α_(v) integrinsincluding α_(v)b₃ and/or α_(IIb)β₃. This Invention satisfies these andother needs.

The therapeutic use of certain quinolizinone derivatives has beendescribed previously. For example, Y. Kitaura et al., in U.S. Pat. No.4,650,804 issued Mar. 17, 1987 have disclosed quinolizinone compoundshaving a tetrazolylcarbamoyl substitiuent which are useful for thetreatment of allergic and ulcer diseases.

J. V. Heck and E. D. Thorsett, in U.S. Pat. No 4,921,857 issued May 1,1990 have disclosed the use of certain 4-oxo-4H-quinolizine-3-carboxylicacids and derivatives thereof for treating bacterial infections.

Y. Kurashiva et Al. in U.S. Pat. No. 4,935,425 issued Jun. 19, 1990 havedisclosed 4H-quinolizin-4-ones for treatment of diseases associated withimmunoglobulin E-antibody formation. However, quinolizinone compoundshave not been described for the use of angiogenesis inhibitors.

Presently, there is a need to identify compounds which bind to integrinreceptors. There is a further need to identify compounds which bind tothe (αvβ3 receptor as well as the αIIbβ3 receptor both individually andcollectively.

Additionally, there is a present need to identify integrin antagonistcompounds which are useful agents for inhibiting and arrestingangiogenesis. The present invention satisfies these and other needs.

SUMMARY OF THE INVENTION

The present invention comprises novel compounds that are effectiveinhibitors of integrins, particularly α_(IIb)β₃ or α_(v) integrins suchas α_(v)β₃ and α_(v)β₅.

The present invention, according to one embodiment, comprises a compoundof formula (I) or formula (II):

or a pharmaceutically acceptable salt, solvate, or metabolic precursorthereof.

According this embodiment of the present invention, one of R1 and R2 is—J—K—L, and the other is H. Furthermore, one of R3 and R4 is —X—Y—Z, andthe other is H.

According to this embodiment of the present invention, J is selectedfrom the group consisting of:

—(CH₂)_(m)—, —(CH₂)_(m)CR⁵═CR⁷(CH₂)_(n)—, —(CH₂)_(m)C≡C(CH₂)_(n)—,—(CH₂)_(m)O(CH₂)_(n)—, —(CH₂)_(m)S(CH₂)_(n)—, —(CH₂)_(m)NR⁵(CH₂)_(n)—,—(CH₂)_(m)CO(CH₂)_(n)—, —(CH₂)_(m)CS(CH₂)_(n)—, —(CH₂)_(m)SO₂(CH₂)_(n)—,—(CH₂)_(m)SO(CH₂)_(n)—, —(CH₂)_(m)C(O)O(CH₂)_(n)—,—(CH₂)_(m)OC(O)(CH₂)_(n)—, —(CH₂)_(m)SO₂NR⁵(CH₂)_(n)—,—(CH₂)_(m)NR⁵SO₂(CH₂)_(n)—, —(CH₂)_(m)CONR⁵(CH₂)_(n)—,—(CH₂)_(m)NR⁵CO(CH₂)_(n)—, —(CH₂)_(m)NR⁵(CH₂)_(n)CONH—,—(CH₂)_(m)O(CH₂)_(n)CONH—, —(CH₂)_(m)NH(CH₂)_(n)SCSNR⁵—,—(CH₂)_(m)NH(CH₂)_(n)SCNHNH₂—, a heterocycle optionally linked by anamine, where m and n are independently integers from 0-6. R⁵ and R⁷ of Jare independently selected from the group consisting of hydrogen,C₁₋₁₀alkyl, C₁₋₁₀alkenyl, C₁₋₁₀alkynyl, C₀₋₈alkylaryl, andC₃₋₁₀cycloalkyl.

According to this embodiment, K is selected from the group consistingof:

—C₁₋₈alkyl-, —C₃₋₁₅cycloalkyl-, —C₆₋₁₅aryl-, —C₆₋₁₅aryl-C₁₋₈alkyl-,—C₁₋₈alkyl-C₆₋₁₅aryl-, —C₁₋₈alkenyl-, —C₁₋₈alkynyl-, —(CH₂)_(q)NR⁶—,—CONR⁶—, —NHC(O)OCH₂—C₆₋₈aryl-, —CNHNH₂—, a heterocycle and an aminelinked heterocycle; L is selected from the group consisting of —H,—C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl, a 5-10 member heterocycle, —C₆₋₁₀aryl,—C₁₋₁₀alkyl-C₆₋₁₀aryl, —NHR¹², —NR¹³C(N)NHR¹², —C(N)NHR¹², —C(O)NHR¹²,—NR¹³C(O)NHR¹², —SC(N)NHR¹², —SC(S)NHR¹², —OC(N)NHR¹², —OC(O)NHR¹² and—C(O)OR¹².

In the definition of K, q is an integer of between 0 and 6.

R⁶ and R¹³ of K are independently selected from the group consisting ofhydrogen, C₁₋₁₀alkyl, C₁₋₁₀alkenyl, C₁₋₁₀alkynyl, C₀₋₈alkylaryl, andC₃₋₁₀cycloalkyl. R¹² is independently selected from the group consistingof —C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl, a —C₀₋₈alkyl-C₆₋₁₀aryl, or a 5-10member heterocycle optionally linked by a C₁₋₁₀alkyl or an amine.

According to this embodiment, X is selected from the group consistingof:

—(CH₂)_(o)—, —(CH₂)_(o)CR⁵═CR⁷(CH₂)_(p)—, —(CH₂)_(o)C≡C(CH₂)_(p)—,—(CH₂)_(o)O(CH₂)_(p)—, —(CH₂)_(o)S(CH₂)_(p)—, —(CH₂)_(o)NR⁵(CH₂)_(p)—,—(CH₂)_(o)CO(CH₂)_(p)—, —(CH₂)_(o)CS(CH₂)_(p)—, —(CH₂)_(o)SO₂(CH₂)_(p)—,—(CH₂)_(o)SO(CH₂)_(p)—, —(CH₂)_(o)C(O)O(CH₂)_(p)—,—(CH₂)_(o)OC(O)(CH₂)_(p)—, —(CH₂)_(o)SO₂NR⁵(CH₂)_(p)—,—(CH₂)_(o)NR⁵SO₂(CH₂)_(p)—, —(CH₂)_(o)CONR⁵(CH₂)_(p)—,—(CH₂)_(o)NR⁵CO(CH₂)_(p)—, —(CH₂)_(o)NR⁵CONR⁷(CH₂)_(p)—,—(CH₂)_(o)NR⁵(CH₂)_(p)CONH—, —(CH₂)_(o)O(CH₂)_(p)CONH—, —(CH₂)_(o)NH(CH₂)_(p)SCSNR⁵—, and —(CH₂)_(o)NH(CH₂)_(p)SCNHNH—, where o and p areindependently integers from 0-6.

Additionally, R⁵ and R⁷ of X are independently selected from the groupconsisting of hydrogen, C₁₋₁₀alkyl, C₁₋₁₀alkenyl, C₁₋₁₀alkynyl,C₀₋₈alkylaryl, and C₃₋₁₀cycloalkyl.

According to this embodiment, Y is selected from the group consistingof:

—(CH₂)_(q)—, C₆₋₈aryl-, a C₃₋₁₀cycloalkyl or

where q and r of Y are independently integers of 0-4 and the sum of sand t is an integer of between 4 and 8.

As defined above, R⁸, R⁹, R¹⁰, and R¹¹ are independently selected fromthe group consisting of H, alkyl, alkenyl, alkynyl, —NR⁵SO₂C₆₋₁₀aryl,C₆₋₁₀aryl-C₁₋₆alkyl-C₆₋₁₀aryl, a 5-10 member heterocycle, an aminelinked 5-10 member heterocycle, and a 5-10 member heterocycle linked bya C₁₋₆alkyl.

Z, of this embodiment, is selected from the group consisting of —H,—COOH, —C(O)OR¹⁴ and —SO₂R¹⁴, R¹⁴ is selected from the group consistingof —C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl, a —C₀₋₈alkyl-C₆₋₁₀aryl, or a 5-10member heterocycle optionally linked by a C₁₋₁₀alkyl or an amine.

Other embodiments of the present invention include specific compoundsand general formula disclosed in the detailed description below.

Another aspect of the invention is a process for preparing a compound offormula I or II. The method comprises preparing a

Compound according to Scheme A herein. Other embodiments of theinvention include preparation of compounds according to any of theschemes or processes disclosed in the detailed description below.

Another aspect of the present invention includes a method for treatmentof cancer comprising administering a pharmaceutically effective amountof the compound of formula I or II as defined herein to a patient, Otherembodiments of the invention include methods of treatment as set forthin the detailed description.

Yet another aspect of the present invention includes a method fortreatment of tumors comprising administering a pharmaceuticallyeffective amount of the compound of formula I or II as defined herein toa patient.

Yet another aspect of the present invention includes a method forinhibiting an α_(v)β₃, α_(v)β₅ or α_(IIb)β₃ integrin in vivo comprisingadministering a pharmaceutically effective amount of the compound offormula I or II to a patient.

List of Schemes:

Scheme A: Preparation of a 7,3 Quinolizinone Framework

Scheme B: Preparation of a 7,2 and 8,2 —Quinolizinone Framework

Scheme C: Preparation of a 7,2 and 8,2 Substituted QuinolizinoneIntegrin Inhibitors

Scheme D: Preparation of a 7 or 8 Aminomethyl Linked QuinolizinoneFramework

Scheme E: Preparation of a 7 or 8 Aminomethyl LinkedTetrahydroquinolizinone Framework

Scheme F: Preparation of a 8,3 and 8,2 Substituted Quinolizinone SeriesBearing an Amino Linker in the —L—K—J Group.

Scheme G: Solid Phase Approach Used to Synthesize the 8,3 SeriesQuinolizinones

DETAILED DESCRIPTION OF THE INVENTION

The present invention comprises novel compounds that are effectiveinhibitors of integrins including α_(v) and/or α_(IIb)β₃ integrins aswell as an effective medicament for the inhibition of angiogenesis andthereby treatment of tumors and cancer.

One embodiment of the present invention comprises a compound of formula(I) or formula (II):

or a pharmaceutically acceptable salt, solvate, or metabolic precursorthereof.

According to this embodiment, one of R1 and R2 is —J—K—L, and the otheris H. Furthermore, one of R3 and R4 is —X—Y—Z, and the other is H.

According to this embodiment, J is selected from the group consistingof:

—(CH₂)_(m)—, —(CH₂)_(m)CR⁵═CR⁷(CH₂)_(n)—, —(CH₂)_(m)C≡C(CH₂)_(n)—,—(CH₂)_(m)O(CH₂)_(n)—, —(CH₂)_(m)S(CH₂)_(n)—, —(CH₂)_(m)NR⁵(CH₂)_(n)—,—(CH₂)_(m)CO(CH₂)_(n)—, —(CH₂)_(m)CS(CH₂)_(n)—, —(CH₂)_(m)SO₂(CH₂)_(n)—,—(CH₂)_(m)SO(CH₂)_(n)—, —(CH₂)_(m)C(O)O(CH₂)_(n)—,—(CH₂)_(m)OC(O)(CH₂)_(n)—, —(CH₂)_(m)SO₂NR⁵(CH₂)_(n)—,—(CH₂)_(m)NR⁵SO₂(CH₂)_(n)—, —(CH₂)_(m)CONR⁵(CH₂)_(n)—,—(CH₂)_(m)NR⁵CO(CH₂)_(n)—, —(CH₂)_(m)NR⁵(CH₂)_(n)CONH—,—(CH₂)_(m)O(CH₂)_(n)CONH—, —(CH₂)_(m)NH(CH₂)_(n)SCSNR⁵—,—(CH₂)_(m)NH(CH₂)_(n)SCNHNH₂—, and a heterocycle optionally linked by anamine, where m and n are independently integers from 0-6. R⁵ and R⁷ of Jare independently selected from the group consisting of hydrogen,C₁₋₁₀alkyl, C₁₋₁₀alkenyl, C₁₋₁₀alkynyl, C₁₋₈alkylaryl, andC₃₋₁₀cycloalkyl.

According to this embodiment, K is selected from the group consistingof:

—C₁₋₈alkyl-, —C₃₋₁₅cycloalkyl-, —C₆₋₁₅aryl-, —C₆₋₁₅aryl-C₁₋₈alkyl-,—C₁₋₈alkyl-C₆₋₁₅aryl-, —C₁₋₈alkenyl-, —C₁₋₈alkynyl-, —(CH₂)_(q)NR⁶—,—CONR⁶—, —NHC(O)OCH₂—C₆₋₈ aryl-, —CNHNH₂—, a heterocycle and an aminelinked heterocycle, where q of K is an integer between 0 and 6.

Additionally, L is selected from the group consisting of

—H, —C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl, a 5-10 member heterocycle,—C₆₋₁₀aryl, —C₁₋₁₀ alkyl-C₆₋₁₀aryl, —NHR¹², —NR¹³C(N)NHR¹², —C(N)NHR¹²,—C(O)NHR¹², —NR¹³C(O)NHR¹², —SC(N)NHR¹², —SC(S)NHR¹², —OC(N)NHR¹²,—OC(O)NHR¹², and —C(O)OR¹².

R⁶ and R¹³ of K are independently selected from the group consisting ofhydrogen, C₁₋₁₀alkyl, C₁₋₁₀alkenyl, C₁₋₁₀alkynyl, C₀₋₈alkylaryl, andC₃₋₁₀cycloalkyl. R¹² is independently selected from the group consistingof —C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl, a —C₀₋₈alkyl-C₆₋₁₀aryl, and a 5-10member heterocycle optionally linked by a C₁₋₁₀alkyl or an amine.

According to this embodiment, X is selected from the group consistingof:

—(CH₂)_(o)—, —(CH₂)_(o)CR⁵═CR⁷(CH₂)_(p)—, —(CH₂)_(o)C≡C(CH₂)_(p)—,—(CH₂)_(o)O(CH₂)_(p)—, —(CH₂)_(o)S(CH₂)_(p)—, —(CH₂)_(o)NR⁵(CH₂)_(p)—,—(CH₂)_(o)CO(CH₂)_(p)—, —(CH₂)_(o)CS(CH₂)_(p)—, —(CH₂)_(o)SO₂(CH₂)_(p)—,—(CH₂)_(o)SO(CH₂)_(p)—, —(CH₂)_(o)C(O)O(CH₂)_(p)—,—(CH₂)_(o)OC(O)(CH₂)_(p)—, —(CH₂)_(o)SO₂NR⁵(CH₂)_(p)—,—(CH₂)_(o)NR⁵SO₂(CH₂)_(p)—, —(CH₂)_(o)CONR⁵(CH₂)_(p)—,—(CH₂)_(o)NR⁵CO(CH₂)_(p)—, —(CH₂)_(o)NR⁵CONR⁷(CH₂)_(p)—,—(CH₂)_(o)NR⁵(CH₂)_(p)CONH—, —(CH₂)_(o)O(CH₂)_(p)CONH—,—(CH₂)_(o)NH(CH₂)_(p)SCSNR⁵—, and —(CH₂)_(o)NH(CH₂)_(p)SCNHNH₂—, where oand p are independently integers from 0-6. Additionally, R⁵ and R⁷ of Xare independently selected from the group consisting of hydrogen,C₁₋₁₀alkyl, C₁₋₁₀alkenyl, C₁₋₁₀alkynyl, C₀₋₈alkylaryl, andC₃₋₁₀cycloalkyl.

According to this embodiment, Y is selected from the group consistingof:

—(CH₂)_(q)—, C₆₋₈aryl-, a C₃₋₁₀cycloalkyl and

where q and r of Y are independently integers of 0-4 and the sum of sand t is an integer of between 3 and 8.

As defined above, R⁸, R⁹, R¹⁰ and R¹¹ are independently selected fromthe group consisting of H, alkyl, alkenyl, alkynyl, —NR⁵SO₂C₆₋₁₀aryl,C₆₋₁₀aryl, C₁₋₆alkyl-C₆₋₁₀aryl, a 5-10 member heterocycle, an aminelinked 5-10 member heterocycle, and a 5-10 member heterocycle linked bya C₁₋₆alkyl.

Z, of this embodiment, is selected from the group consisting of —H,—COOH, —C(O)OR¹⁴ and —SO₂R¹⁴. R¹⁴ is selected from the group consistingof —C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl, a —C₀₋₈alkyl-C₆₋₁₀aryl, or a 5-10member heterocycle optionally linked by a C₁₋₁₀alkyl and an amine.

In another embodiment, the present invention comprises a compound offormula I otherwise as previously defined.

Another embodiment, of the present invention comprises the compound offormula II otherwise as previously defined.

In another embodiment, the present invention comprises a compound offormula I or formula II as previously defined except that R1 and R3 areboth H and R2 is —J—K—L and R4 is —X—Y—Z.

In another embodiment, the present invention comprises a compound offormula I or formula II as previously defined except that R1 and R4 areboth H and R2 is —J—K—L and R3 is —X—Y—Z.

In another embodiment, the present invention comprises a compound offormula I or formula II as previously defined except that R2 and R3 areboth H and R1 is —J—K—L and R4 is —X—Y—Z.

In another embodiment, the present invention comprises a compound offormula I or formula II as previously defined except that R2 and R4 areboth H and R2 is —J—K—L and R3 is —X—Y—Z.

In another embodiment, the present invention comprises a compound offormula I or formula II as previously defined except that J is selectedfrom the group consisting of:

—(CH₂)_(m)—, —(CH₂)_(m)CR⁵═CR⁷(CH₂)_(n)—, —(CH₂)_(m)C≡C(CH₂)_(n)—,—(CH₂)_(m)O(CH₂)_(n)—, —(CH₂)_(m)S(CH₂)_(n)—, —(CH₂)_(m)NR⁵(CH₂)_(n)—,—(CH₂)_(m)CO(CH₂)_(n)—, —(CH₂)_(m)CS(CH₂)_(n)—, —(CH₂)_(m)SO₂(CH₂)_(n)—,—(CH₂)_(m)SO(CH₂)_(n)—, —(CH₂)_(m)C(O)O(CH₂)_(n)—,—(CH₂)_(m)OC(O)(CH₂)_(n)—, —(CH₂)_(m)SO₂NR⁵(CH₂)_(n)—,—(CH₂)_(m)NR⁵SO₂(CH₂)_(n)—, —(CH₂)_(m)CONR⁵(CH₂)_(n)—,—(CH₂)_(m)NR⁵CO(CH₂)_(n)—, and an amine linked 5-10 member heterocycle,where m and n are independently integers from 0-6.

In another embodiment, the present invention comprises formula I orformula II as previously defined except that J is selected from thegroup consisting of

—(CH₂)_(m)—, —(CH₂)_(m)C≡C(CH₂)_(n)—, —(CH₂)_(m)CR⁵═CR⁷(CH₂)_(n)—,—(CH₂)_(m)O(CH₂)_(n)—, —(CH₂)_(m)S(CH₂)_(n)—, —(CH₂)_(m)NR⁵(CH₂)_(n)—,and an amine linked 5-10 member heterocycle; and wherein m and n areindependently integers from 0-3.

According to this embodiment, m is preferably an integer between 0-1 andmore preferably m is 0. According to this embodiment, n is preferably aninteger between 0-1, and most preferably n is 0.

Also according to one aspect of this embodiment, R⁵ and R⁷ arepreferably —H or —CH₃ and most preferably R⁵ and R⁷ are —H.

In another embodiment, the present invention comprises formula I orformula II as previously defined except that K is selected from thegroup consisting of:

—C₁₋₈alkyl-, —C₃₋₁₅cycloalkyl-, —C₆₋₁₅aryl-, —C₆₋₁₅aryl-C₁₋₈alkyl-,—C₁₋₈alkyl-C₆₋₁₅aryl-, —C₁₋₈alkenyl—, —C₁₋₈alkynyl-, a 5-15 memberheterocycle, and an amine linked 5-15 member heterocycle.

In another embodiment, the present invention comprises formula I orformula II as previously defined except that K is a —C₁₋₈alkyl- or a—C₃₋₁₅ cycloalkyl-.

In another embodiment, K is preferably a —C₁₋₃alkyl- and most preferablya —C₁alkyl-.

In another embodiment, the present invention comprises formula I orformula II as previously defined except that K is preferably a—C₅₋₈cycloalkyl-.

In another embodiment, the present invention comprises formula I orformula II as previously defined except that L is selected from thegroup consisting of a 5-10 member heterocycle, —NHR¹², —NR¹³C(N)NHR¹²,—C(N)NHR¹², —C(O)NHR¹², —NR¹³C(O)NHR¹², —SC(N)NHR¹², —SC(S)NHR¹²,—OC(N)NHR¹², —OC(O)NHR¹², and —C(O)OR¹².

In another embodiment, the present invention comprises formula I orformula II as previously defined except that L is selected from thegroup consisting of:

a 5-10 member heterocycle, C₆₋₁₀aryl, —NH₂R¹², —NR¹³C(N)NHR¹²,—C(N)NHR¹², —C(O)NHR¹², —NR¹³C(O)NHR¹², —SC(N)NHR¹², —SC(S)NHR¹², and—OC(N)NHR¹².

According to one aspect of this embodiment, R¹³ is preferably aC₁₋₅alkyl or H; and most preferably R¹³ is H.

In another embodiment, the present invention comprises formula I orformula II as previously defined except that R¹² is selected from thegroup consisting of —C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl, or a—C₀₋₈alkyl-C₆₋₁₀aryl, and a 5-10 member heterocycle optionally linked bya C₁₋₁₀alkyl.

In another embodiment, the present invention comprises formula I orformula II as previously defined except that R¹² is a 5-6 memberaromatic heterocycle containing between one and three heteroatomsoptionally linked by a C₁₋₂alkyl or an amine.

In another embodiment, R¹² is a C₆aryl optionally linked by a C₁₋₂alkylor an amine.

In another embodiment, the present invention comprises formula I orformula II as previously defined except that R¹² is a heterocycleoptionally linked by a C₁₋₂alkyl or an amine, wherein said heterocycleis selected from the group consisting of pyridine, pyrimidine,piperazine, pyrrole, furan, imidazole, oxazole, pyrazole, pyrroline, andpyrrolidine.

In another embodiment, the present invention comprises formula I orformula II as previously defined except that X is selected from thegroup consisting of:

—(CH₂)_(o)SO₂(CH₂)_(p)—, —(CH₂)_(o)C(O)O(CH₂)_(p)—,—(CH₂)_(o)OC(O)(CH₂)_(p)—, —(CH₂)_(o)SO₂NR⁵(CH₂)_(p)—,—(CH₂)_(o)NR⁵SO₂(CH₂)_(p)—, —(CH₂)_(o)CONR⁵(CH₂)_(p)—,—(CH₂)_(o)NR⁵CO(CH₂)_(p)—, —(CH₂)_(o)NR⁵CONR⁷(CH₂)_(p)—, where o and pare independently integers from 0-6.

In another embodiment, the present invention comprises formula I orformula II as previously defined except that X is selected from thegroup consisting of —(CH₂)_(o)CONH—, and —(CH₂)_(o)NR⁵CONR⁷(CH₂)_(p)—.

In another embodiment, o is preferably an integer from 0-2; p is andinteger from 0-2. Most preferably, according to one embodiment, o and pare 0.

According to one embodiment R⁵ and R⁷ are independently H or aC₁₋₄alkyl. Most preferably, according to this embodiment, R⁵ and R⁷ areboth H.

In another embodiment, the present invention comprises formula I orformula II as previously defined except that Y is selected from thegroup consisting of:

According to one embodiment, q is an integer of 0-2; most preferably, qis 0.

According to one embodiment, r is an integer of 0-2; and most preferablyr is 0.

According to one embodiment, the sum of s and t is an integer of between3 and 5, and is most preferably 4.

In another embodiment, the present invention comprises formula I orformula II as previously defined except that Y is

wherein q and r are independently integers of 0-1;

wherein R⁸ , R⁹, R¹⁰, and R¹¹ are independently selected from the groupconsisting of H, —NR⁵SO₂C₆₋₁₀aryl, C₆₋₁₀aryl, C₁₋₆alkyl-C₆₋₁₀aryl,NR⁵C₆₋₁₀aryl, a 5-10 member heterocycle, a 5-10 member heterocyclelinked by a C₁₋₆alkyl and an amine linked 5-10 member heterocycle.

In another embodiment, the present invention comprises formula I orformula II as previously defined except that one of R⁸ and R⁹ is not Hand the other is H, and R¹⁰ and R¹¹ are both H.

In another embodiment, the present invention comprises formula I orformula II as previously defined except that one of R⁸ and R⁹ isselected from the group consisting of:

—NR⁵SO₂C₆aryl, C₆aryl, C₁₋₂alkyl-C₆aryl, a 6 member heterocycle, a 6member heterocycle linked by a C₁₋₂alkyl, and an amine linked 6 memberheterocycle.

In another embodiment, the present invention comprises formula I orformula II as previously defined except that one of R⁸ and R⁹ is eithera six member heterocycle containing 0-3 nitrogen atoms or a phenylsubstituted alternatively with one to three substituents selected fromthe group consisting of C₁₋₄alkyl, flourine, chlorine, bromine, andiodine.

In another embodiment, the present invention comprises formula I orformula II as previously defined except that one of said R⁸ and R⁹ is aheterocycle optionally linked by a C₁₋₂alkyl or an amine, wherein saidheterocycle is selected from the group consisting of pyridine,pyrimidine, piperazine, pyrrole, furan, imidazole, oxazole, pyrazole,piperidine, morpholine, thiomorpholine, thiophene, pyrroline, andpyrrolidine.

In another embodiment, the present invention comprises formula I orformula II as previously defined except that Z is selected from thegroup consisting of —H, —COOH, and —C(O)OR¹⁴.

In another embodiment, the present invention comprises formula I orformula II as previously defined except that Z is selected from thegroup consisting of —H and —COOH.

In yet another embodiment, the invention is a pharmaceutical compositioncomprising a compound of formula I and II as previously defined and apharmaceutically acceptable excipient.

Another embodiment of the present invention includes a compound offormula I or formula II as defined as follows: J, of this embodiment isselected from the group consisting of: —(CH₂)_(m)—,—(CH₂)_(m)O(CH₂)_(n)—, and —(CH₂)_(m)NR⁵(CH₂)_(n); m and n areindependently integers between 0 and 6. R⁵ and R⁷ for J areindependently selected from the group consisting of hydrogen and C₁₋₄alkyl.

K of this embodiment is selected from the group consisting of:

—C₁₋₈alkyl-, a —C₃₋₁₅ cycloalkyl-, and a 5-10 member heterocycle.

L of this embodiment is selected from the group consisting of:

a 5-10 member heterocycle, C₆₋₁₀aryl, —NH₂R¹², —NR¹³C(N)NHR¹²,—C(N)NHR¹², —C(O)NHR¹², —NR¹³C(O)NHR¹², —SC(N)NHR¹², —SC(S)NHR¹², and—OC(N)NHR¹²; R¹³ of L is selected from the group consisting of hydrogenand C₁₋₄ alkyl. R¹² of L is selected from the group consisting of a—C₁₋₄alkyl, a —C₀₋₄alkyl-C₆₋₇aryl and a 5-10 member heterocycleoptionally linked by a C₁₋₁₀alkyl or an amine.

X of this embodiment is selected from the group consisting of:

—(CH₂)_(o)CONH—, —(CH₂)_(o)NR⁵CONR⁷(CH₂)_(p)—; o and p are independentlyintegers from 0 to 6. R⁵ and R⁷ of X are independently selected from thegroup consisting of hydrogen and C₁₋₄ alkyl.

Y of this embodiment is selected from the group consisting of:—(CH₂)_(q)—,

Accordingly, q, r, s, and t of Y are independently integers of 0-4. Thesum of s and t is an integer between 3 and 8. R⁸, R⁹, R¹⁰, and R¹¹ areindependently selected from the group consisting of H. —NR⁵SO₂C₆₋₁₀aryl,C₆₋₁₀aryl, C₁₋₆alkyl-C₆₋₁₀aryl, —NR⁵C₆₋₁₀aryl, a 5-10 memberheterocycle, a 5-10 member heterocycle linked by a C₁₋₆alkyl and anamine linked 5-10 member heterocycle.

Z of this embodiment is selected from the group consisting of —H and—COOH.

According to one embodiment of the present invention, the compound is offormula I and is otherwise as previously defined.

According to one embodiment of the present invention, the compound is offormula II and is otherwise as previously defined.

According to an aspect of this embodiment, m is an integer between 0-1.

According to an aspect of this embodiment, n is an integer between 0-1.

In another embodiment, the present invention comprises formula I orformula II as previously defined except that R⁵ and R⁷ of J areindependently —H or a C₁₋₄alkyl; most preferably, —H.

In another embodiment, the present invention comprises formula I orformula II as previously defined except that K is a —C₁alkyl-.

In another embodiment, the present invention comprises formula I orformula II as previously defined except that K is a C₅₋₈cycloalkyl-.

In another embodiment, the present invention comprises formula I orformula II as previously defined except that R¹³ of L is a C₁₋₅alkyl orH.

In another embodiment, the present invention comprises formula I orformula II as previously defined except that R¹² of L is a 5-6 memberaromatic heterocycle containing between one and three heteroatomsoptionally linked by a C₁₋₂alkyl or an amine.

In another embodiment, the present invention comprises formula I orformula II as previously defined except that R¹² of L is a C₆aryloptionally linked by a C₁₋₂alkyl or an amine.

In another embodiment, the present invention comprises formula I orformula II as previously defined except that o of X is an integer from0-1.

In another embodiment, the present invention comprises formula I orformula II as previously defined except that p of X is an integer from0-1.

In another embodiment, the present invention comprises formula I orformula II as previously defined except that R⁵ and R⁷ of X areindependently H or a C₁₋₄alkyl.

In another embodiment, the present invention comprises formula I orformula II as previously defined except that q and r of Y areindependently integers of 0-1.

In another embodiment, the present invention comprises formula I orformula II as previously defined except that the sum of s and t is 4.

In another embodiment, the present invention comprises formula I orformula II as previously defined except that Y is

wherein q and r are independently integers of 0-1;

wherein R⁸, R⁹, R¹⁰, and R¹¹ are independently selected from the groupconsisting of H, —NR⁵SO₂C₆₋₁₀aryl, C₆₋₁₀aryl, C₁₋₆alkyl-C₆₋₁₀aryl,NR⁵C₅₋₁₀aryl, a 5-10 member heterocycle, a 5-10 member heterocyclelinked by a C₁₋₆alkyl and an amine linked 5-10 member heterocycle.

In another embodiment, the present invention comprises formula I orformula II as previously defined except that R⁸ and R⁹ is not H and theother is H, and R¹⁰ and R¹¹ are both H.

In another embodiment, the present invention comprises formula I orformula II as previously defined except that R⁸ and R⁹ is selected fromthe group consisting of:

—NR⁵SO₂C₆aryl, C₆aryl, C₁₋₂alkyl-C₆aryl, a 6 member heterocycle, a 6member heterocycle linked by a C₁₋₂alkyl, and an amine linked 6 memberheterocycle.

In another embodiment, the present invention comprises formula I orformula II as previously defined except that R⁸ and R⁹ is either a sixmember heterocycle containing 0-3 nitrogen atoms or a phenyl substitutedalternatively with one to three substituents selected from the groupconsisting of C₁₋₄alkyl, flourine, chlorine, bromine, and iodine.

In another embodiment, the present invention comprises formula I orformula II as previously defined except that R⁸ and R⁹ is a heterocycleoptionally linked by a C₁₋₂alkyl or an amine, wherein said heterocycleis selected from the group consisting of pyridine, pyrimidine,piperazine, pyrrole, furan, imidazole, oxazole, pyrazole, pyrroline,piperidine, morpholine, thiomorpholine, and thiophene and pyrrolidine.

In another embodiment, the present invention comprises formula I orformula II as previously defined except that R3 is H and R4 is JKL.According to this embodiment, J is selected from the group consisting of—(CH₂)_(m)— and —(CH₂)_(m)O(CH₂)_(n)—, wherein m and n are independentlyintegers from 0-3. K is a —C₁₋₈alkyl-. L is selected from the groupconsisting of —NH₂ and

According to this embodiment, X is —(CH₂)_(o)CONH—, o is an integer from0-3.

In another embodiment, Y is selected from the group consisting of:

wherein q, r, s, and t are independently integers of 0-4, and the sum ofs and t is 4. Z is —COOH. R¹⁵, R¹⁶, and R¹⁷ are independently selectedfrom the group consisting of —H, C₁₋₄alkyl and halogen (F, Cl, Br, andI).

In another embodiment, the present invention comprises formula I orformula II as previously defined except that R3 is H and R4 is JKL.According to this embodiment, J is selected from the group consistingof:

—(CH₂)_(m)O(CH)_(n)—, where m and n are independently integers from 0-3.

According to this embodiment, K is selected from the group consisting of—C₁₋₈alkyl-. L is selected from the group consisting of —NH₂,

According to this embodiment, X is selected from the group consistingof: —(CH₂)_(o)CONH— and —(CH₂)_(o)NR⁵CONR⁷(CH₂)_(p)—, where o and p areindependently integers from 0-3.

Also according to this embodiment, Y is selected from the groupconsisting of:

where q, r, s, and t are independently integers of 0-4, and wherein thesum of s and t is 4. Additionally, R¹⁵, R¹⁶, and R¹⁷ are independentlyselected from the group comprising C₁₋₄alkyl, H, and halogen (F, Cl, Br,I).

Also according to this embodiment, R⁵, R⁶, and R⁷ are, for eachstructure they represent, independently selected from the groupconsisting of: hydrogen and C₁₋₄ alkyl.

According to this embodiment, Z is —COOH.

In another embodiment, the present invention comprises formula I orformula II as previously defined except that R1 is XYZ and R2 is H.According to this embodiment, R3 is JKL and R4 is H. J is—(CH₂)_(m)O(CH₂)_(n)—, where m and n are independently integers from0-3.

K is —C₁₋₈alkyl-; L is selected from the group consisting of

—NH₃ and

According to this embodiment, X is —(CH₂)_(o)CONH—, where o is aninteger from 0-3. Y is selected from the group consisting of:

R¹⁵, and R¹⁶, R¹⁷ are independently selected from the group comprisingC₁₋₄alkyl, H, and halogen (F, Cl, Br, I).

According to this embodiment, Z is —COOH.

In another embodiment, the present invention comprises formula I orformula II as previously defined except that R1 is XYZ, R2 is H, R3 isH, and R4 is JKL. According to this embodiment, j is selected from thegroup consisting of:

—N—, —N(CH₃)—, and an amine linked heterocycle.

K is selected from the group consisting of:

—C₁₋₈alkyl- and —C₃₋₁₅cycloalkyl-.

L is selected from the group consisting of

—NH₂,

According to this embodiment, X is —(CH₂)_(o)CONH—, where o is aninteger from 0-3. Y is selected from the group consisting of:

wherein R¹⁵, R¹⁶, and R¹⁷ are independently selected from the groupconsisting of C₁₋₄alkyl, H, and halogen (F, Cl, Br, I).

According to this embodiment, Z is —COOH.

In another embodiment, the present invention comprises formula I orFormula II as previously defined except that L is selected from thegroup consisting of —NH₂,

In another embodiment, the present invention comprises formula I orformula II as previously defined except that Y is selected from thegroup consisting of

wherein q, r, s, and t are independently integers of 0-4 and the sum ofs and t is an integer between 3 and 8. Additionally, R¹⁵, R¹⁶, and R¹⁷are independently selected from the group consisting of —H, C₁₋₄alkyland halogen (F, Cl, Br, and I)

Particularly, according to one embodiment the present invention is acompound is of the following formula I or II:

wherein one of R1 and R2 is —J—K—L, and the other is H; and one of R3and R4 is —X—Y—Z, and the other is H;

wherein J and X are independently selected from the group consisting of:

—(CH₂)_(m)—; —(CH₂)_(m)O(CH₂)_(n)—; —(CH₂)_(m)NR⁵(CH₂)_(n)—;—(CH₂)_(m)SO₂(CH₂)_(n)—; —(CH₂)_(m)S(CH₂)_(n)—; —(CH₂)_(m)SO(CH₂)_(n)—;—(CH₂)_(m)CO₂R⁵—; —(CH₂)_(m)SO₂NR⁵(CH₂)_(n)—;—(CH₂)_(m)NR⁵SO₂(CH₂)_(n)—; —(CH₂)_(m)CR⁵═CR⁷(CH₂)_(n)—;—(CH₂)_(m)CONH—; —(CH₂)_(m)NR⁵(CH₂)_(n)CONH—; —(CH₂)_(m)O(CH₂)_(n)CONH—;—(CH₂)_(m)N(CH₂)_(n)SCSNHR⁵—; —(CH₂)_(m)N(CH₂)_(n)SCNHNH₂—; and aheterocyclic ring, which is unsubstituted or substituted with —CNR⁵NH₂;

wherein m and n are independently integers from 0-6;

or —X—Y—Z together are Cl or COOH;

wherein K is selected from the group consisting of: hydrogen, C₁₋₈alkyl,C₆₋₁₅aryl C₁₋₈ alkyl, C₁₋₈ alkenyl; C₁₋₈ alkynyl; C₃₋₁₅ cycloalkyl; NH₂;NHHeterocycle; HCONHR⁶; NCO₂CH₂C₆₋₈aryl; NR⁵CNHNH₂; andHeterocycle(CH₂)_(m)COOR⁵; wherein Y is selected from the groupconsisting of: hydrogen, CR⁸R⁹CR¹⁰R¹¹COOR⁵; C₆₋₈aryl; C₃₋₁₀ cycloalkylwhich is unsubstituted or substituted with COOH or NR⁵CNHNH₂;Heterocycle(CH₂)_(m)COOR⁵; (CH)qCH(CH)r;

wherein q, r, s, and t are independently integers of 0-4;

L and Z are independently selected from the group consisting of H, C₁₋₁₀alkyl, and C₃₋₁₀ cycloalkyl; wherein R⁵, R⁶ and R⁷ are independentlyselected from the group consisting of:

hydrogen; C₁₋₁₀ alkyl; aryl C₀₋₈ alkyl; pyridine; and C₃₋₁₀ cycloalkylwhich is unsubstituted or substituted with COOH or NR⁵CNHNH₂;

and R⁸, R⁹, R¹⁰, and R¹¹ are independently selected from the groupconsisting of

H; NR⁵SO₂C₆₋₁₀ Aryl; NHHeterocycle; and C₆₋₁₀ Aryl;

or a pharmaceutically acceptable salt, solvate, or metabolic precursorthereof.

Particular compounds according to the present invention include thefollowing compounds which name has been provided by the AUTONOM™software:

Compound I:2-benzylsulfonylamino-3-{[7-(5-aminopentyloxy)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-propionicacid TFA salt.

Compound II:2-benzylsulfonylamino-3-{[7-(5-guanidinopentyloxy)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-propionicacid hydrochloride.

Compound III:2-benzylsulfonylamino-3-{[7-(3-aminopentyloxy)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-propionicacid TFA salt.

Compound IV:2-benzylsulfonylamino-3-{[7-(5-guanidinopropyloxy)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-propionicacid hydrochloride.

Compound V:′(trans)-2-{[7′-(3″-amino-propoxy)-4′-oxo-4′H-quinolizine-3′-carbonyl]-amino}-cyclohexanecarboxylicacid trifluoroacetic acid salt.

Compound VI:′7(r,s)-3-benzoyloxycarbonylaminopropyl)oxo-3-carboxy-3-phenylsulfonylamino-1-yl)aminocarbonylaminoethyl)quinolizin-4-one.

Compound VII:′7(r,s)-3-((aminopropyl)oxo-3-carboxy-3-phenylsulphonylamino-1-yl)aminocarbonylaminoethyl)quinolizin-4-one.

Compound VIII:′7(r,s)-((3-guanidinoaminopropyl)oxy-3-carboxy-1pyridyl1-ethyl)aminocarbonylamino)quinolizin-4-one.

Compound IX:2-Benzenesulfonylamino-3-{3-[7-(3-guanidino-propoxy)-4-oxo-4H-quinolizin-3-yl]-ureido}-propionicacid trifluoroacetate.

Compound X:3-Phenyl-3-{[7-(3-benzyl-ureidopropoxy)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-propionicacid.

Compound XI:3-{[7-(3-tert-Butoxycarbonylamino-propoxy)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-3-phenyl-propionicacid ethyl ester.

Compound XII:(S)-2-Benzenesulfonylamino-3-({7-[3-(3-methyl-ureido)-propoxy]-4-oxo-4H-quinolizine-2-carbonyl}-amino)-propionicacid.

Compound XIII: 7-(3-amino-propyloxy)-4-oxo-4H-quinolizine-2-carboxylicacid TFA salt.

Compound XIV:2-Benzenesulfonylamino-3-{[7-(3-amino-propoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionicacid TFA salt.

Compound XV:2-Benzenesulfonylamino-3-{[7-(3-guanidino-propoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionicacid hydrochloride.

Compound XVI:3-{[7-(3-amino-propoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionicacid TFA salt.

Compound XVII:2-Benzenesulfonylamino-3-{[7-(4-amino-butoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionicacid TFA salt.

Compound XVIII:2-Benzenesulfonylamino-3-{[7-(4-guanidino-butoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionicacid hydrochloride.

Compound XIX:2-Benzenesulfonylamino-3-{[7-(4-amino-ethoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionicacid.

Compound XX:2-Benzenesulfonylamino-3-{[7-(4-guanidino-ethoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionicacid.

Compound XXI:3-{[7-(3-Amino-propoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-2—(pyrimidin-2-ylamino)-propionicacid hydrochloride.

Compound XXII:3-{[7-(3-Guanidino-propoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-2—(pyrimidin-2-ylamino)-propionicacid hydrochloride.

Compound XXIII:3-{[7-(3-Amino-propoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-2-(benzenesulfonyl-methyl-amino)-propionicacid trifluoroacetace.

Compound XXIV:2-(Benzenesulfonyl-methyl-amino)-3-{[7-(3-guanidino-propoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionicacid hydrochloride.

Compound XXV:′2-benzenesulfonylamino-3-({4-oxo-7-[3-(pyrimidin-2-ylamino)-propoxy]-4H-quinolizine-2-carbonyl}-amino)-propionicacid

Compound XXVI:3-[(7-Aminomethyl-4-oxo-4H-quinolizine-2-carbonyl)-amino]-2-benzenesulfonylamino-propionicacid

Compound XXVII:2-Benzenesulfonylamino-3-[(7-guanidinomethyl-4-oxo-4H-quinolizine-2-carbonyl)-amino]-propionicacid

Compound XXVIII:3-[(7-Aminomethyl-4-oxo-6,7,8,9-tetrahydro-4H-quinolizine-2-carbonyl)-amino]-2-benzenesulfonylamino-propionicacid

Compound XXXIX:2-Benzenesulfonylamino-3-[(7-guanidinomethyl-4-oxo-6,7,8,9-tetrahydro-4H-quinolizine-2-carbonyl)-amino]-propionicacid

Compound XXX:3-{[8-(3-Amino-propoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-2-benzenesulfonylamino-propionicacid trifluoroacetate.

Compound XXXI:2-Benzenesulfonylamino-3-{[8-(3-guanidino-propoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionicacid hydrochloride.

Compound XXXII:3-{[8-(4-Amino-butoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-2-benzenesulfonylamino-propionicacid trifluoroacetate.

Compound XXXIII:2-Benzenesulfonylamino-3-{[8-(4-guanidino-butoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionicacid hydrochloride.

Compound XXXIV:3-{[8-(5-Amino-pentyloxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-2-benzenesulfonylamino-propionicacid trifluoroacetate.

Compound XXXV:2-Benzenesulfonylamino-3-{[8-(5-guanidino-pentyloxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionicacid hydrochloride.

Compound XXXVI:3-{[8-(2-amino-ethylamino)-4-oxo-4H-quinolizine-3-carbonyl)-amino}-3-phenyl-propionicacid

Compound XXXVII:3-{[8-(2-Carbamimidoylsulfanyl-ethylamino)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-3-phenyl-propionicacid trifluoroacetate.

Compound XXXVIII:3-({4-Oxo-8-[2-(pyridin-3-ylthiocarbamoylsulfanyl)-ethylamino]-4H-quinolizine-3-carbonyl}-amino)-3-phenyl-propionicacid trifluoroacetate.

Compound XXXIX:3-[(8-{Methyl-[2-(N-methyl-guanidino)-ethyl]-amino}-4-oxo-4H-quinolizine-3-carbonyl)-amino]-3-phenyl-propionicacid trifluoroacetate.

Compound XL:3-{[8-(4—Carbamimidoyl-piperazin-1-yl)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-3-phenyl-propionicacid trifluoroacetate.

Compound XLI:3-{[8-(4-Guanidino-cyclohexylamino)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-3-phenyl-propionicacid trifluoroacetate.

Compound XLII:(+/−)-3-(3,5-Dichlorophenyl)-3-((7-guanidinomethyl-4-oxo-4H-quinolizine-2-carbonyl)-amino]-propionicacid trifluoroacetic acid salt.

Compound XLIII:(+/−)-3-[(7-guanidinomethyl-4-oxo-4H-quinolizine-2-carbonyl]-amino)-3-pyridin-3-yl-propionicacid bis-trifluoroacetic acid salt.

Compound XLIV:(+/−)-3-[(7-guanidinomethyl-4-oxo-4H-quinolizine-2-carbonyl)-amino]-2-(pyrimidin-2-ylamino)-propionicacid bis-trifluoroacetic acid salt.

Compound XLV:(S)-2-Benzenesulfonylamino-3-([(7-benzyloxycarbonylamino-methyl)-4-oxo-4H-quinolizine-2-carbonyl]-amino)-propionicacid.

Compound XLVI:(S)-2-Benzenesulfonylamino-3-([4-oxo-7-(pyrimidin-2-ylaminomethyl)-4H-quinolizine-2-carbonyl]-amino)-propionicacid trifluoroacetic acid salt.

Compound XLVII(S)-2-Benzenesulfonylamino-3-{[7-(3-benzyl-ureidomethyl)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionicacid.

Compound XLVIII:(S)-2-Benzyloxycarbonylamino-3-[(7-guanidinomethyl-4-oxo-4H-quinolizine-2-carbonyl)-amino]-propionicacid trifluoroacetic acid salt.

Compound XLIX:(S)-3-[(7-guanidinomethyl-4-oxo-4H-quinolizine-2-carbonyl)-amino]-2-(2,4,6-trimethyl-benzenesulfonylamino)-propionicacid hydrochloride.

The term “quinolizinone” refers to

The definition of quinolizinone also includes a tetrahydraquinolizinonewherein the ring involving atoms 5-10 may also be saturated.

The term “alkyl” as used herein represents a straight or branched,saturated or unsaturated chain having a specified total number of carbonatoms (i.e. C₂ alkyl has two carbon atoms in the chain).

The term “heterocylcle” as used herein represents an aromatic ornon-aromatic hydrocarbon ring structure that contains in the ringstructure one or more heteroatoms (O, S, or N). As used herein the term“linked” heterocycle refers to a heterocycle wherein the ring membersare linked to another chemical structure by a defined structure such asan amine or an alkyl.

The term “between” in defining a range is meant to include the numberthat define the range (eg. between 3 and 7 means all numbers including 3and 7).

It should be understood that reference to the structures representing—J—K—L and K—Y—Z have a left side and a right side. The left side of asubstituent group defining J and X is bound to the quinolizinonescaffoled. The left side of a group defining K and Y bind to J and Xrespectively. The left side of a substituent group defining L and Z bindto K and Y respectively.

The term “phenyl” or “benzene” represents a six member aromatic carboncontaining ring whether or not the ring is a substituent group orotherwise.

The term “amino” includes primary amines i.e. NH₂, secondary amines i.e.NHR, or tertiary amines i.e. N(R)₂ wherein R is C₁₋₄ alkyl. Alsoencompassed by the term are quaternary amines such as —NH₃ ⁺.

The term “guanadino” refers to the following structure:

The term “guanadino containing moiety” refers to a moiety that has onecarbon bound to three nitrogen.

The term “urea” refers generally to the following structure:

The term “urea containing moiety” refers to a moiety that contains acarbon bound to two nitrogen atoms and an oxygen atom.

The term “aryl” as defined herein refers to an aromatic ring havingspecified number of carbons (i.e. C₂ has two carbons) that mayoptionally be substituted with one or more heteroatoms selected from thegroup consisting of O, N, and S.

The term “pyrimidinyl” represents a six member aryl that contains twonitrogen atoms separated by carbon.

The term “sulfonyl” refers to a compound with the following structure:

The above terms also includes salts, esters, and salts of esters of theabove corresponding structures unless designated otherwise.

The term “pharmaceutically acceptable salts” shall mean non-toxic saltsof the compounds of this invention which are generally prepared byreacting the free base with a suitable organic or inorganic acid.Representative salts include the following salts: acetate,benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate,bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate,citrate, dihydrochloride, edetate, edisylate, estolate, esylate,fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate,hexylresorcinate, hydrabramine, hydrobromide, hydrochloride,hydroxynapthoate, iodide, isothionate, lactate, lactobionate, laurate,malate, maleate, mandelate, mesylate, methylbromide, methylnitrate,methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, pamaote,palmitate, panthothenate, phosphate/diphosphate, polygalacturonate,salicylate, stearate, subacetate, succinate, tannate, tartrate,teoclate, tosylate, triethiodide, trifluoroacetate, and valerate.

Compounds illustrated herein may be illustrated with incomplete valence.Such compounds, are intended to represent compounds with completevalence at all atoms. In such an instance where a compound hasincomplete valence, it is intended that that atom has additional —Hatoms bound to it to complete the valence.

Compounds of the present invention are chiral; included within the scopeof the present invention are racemic mixtures and separated enantiomersof the general formula. Furthermore, all diastereoisomers of the generalformula are included in he present scope. Furthermore, hydrates as wellas anhydrous compositions and polymorphs of the general formula arewithin the present invention.

Prodrugs, such as ester derivatives of described compounds, are compoundderivatives which, when absorbed into the bloodstream of a warm-bloodedanimal, cleave in such a manner as to release the drug form and permitthe drug to afford improved therapeutic efficacy.

The term “pharmaceutically effective amount” shall mean that amount of adrug or pharmaceutical agent that will elicit the biological or medicalresponse of a tissue, system or animal that is being sought by aresearcher or clinician.

In the schemes and examples below, various reagent symbols have thefollowing meanings:

BOC: t-butyloxycarbonyl

Pd-C: palladium on activated carbon catalyst

DMF: dimethylformamide

DMSO: dimethylsulfoxide

CBZ: carbobenzyloxy

CH₂Cl₂: methylene chloride

CHCl₃: chloroform

EtOH: ethanol

MeOH: methanol

EtOAc: ethylacetate

HOAc: acetic acid

BOP: Benzotriazol-1-yloxytris (dimethylamino) phosphonium,hexafluorophosphate

EDC: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

Oxone: potassium peroxymonosulfate

TDA: lithium diisopropylamide

PYCLU: chloro-N,N,N′,N,-bis (pentamethylene) formamidiumhexafluorophosphate;

The present invention also includes methods of making compounds offormula I or II or any of the other formulas disclosed herein. Compoundsof the present invention can be synthesized using conventionalpreparative steps and recovery methods known to those skilled in the artof organic chemistry. Synthetic routes according to one or moreembodiments of the invention are illustrated in the following SchemesA-G and described below.

Preparation of a 7,3-Quinolizinone Framework

As per Scheme A, a compound A-1 such as 5-hydroxy-2-methylpyridine istreated with strong base such as n-butyl lithium in an anhydroussolvent, for example THF, at low temperature and then coupled withdiethyl ethoxymethylene malonate. The resulting alkylated product isconverted into 7-hydroxy-4-oxo-4H-quinolizine-3-carboxylic acid ethylester by refluxing in an aromatic solvent such as xylenes. The compoundA-2 such as 7,3-quinolizinone ester is then treated with a strong basesuch as NaH, in an anhydrous solvent, and the resulting anion is reactedwith compatibly functionalised -L—K—J—Lg bearing if necessaryappropriate protecting groups and wherein L′g is a leaving group.Hydrolysis of the ethyl ester is done by treating the compound A-3 suchas.the coupled quinolizinone with an hydroxide such as lithiumhydroxide. The resulting acid compound A-4 is coupled with appropriatelyfunctionalised nucleophiles bearing the —L—K—J in its masked or currentform in a solvent such as DMF in the presence of a coupling reagent suchas (O-(7-azobenzotriazol-1-yl)-1,3,3-tetramethyluroniumhexafluorophosphate), HATU, to provide compound A-5 such asfunctionalised 7,3-quinolozinone. Someone versed in the art of organicsynthesis will recognize that the preparation of A-5 as described inthis invention may require the use of protecting groups compatible withthe synthetic sequence and removed when required. Alternatively and ifmore appropriate, the functionality —X—Y—Z could be introduced firstonto protected quinolizinones A6 as described for A-4 to give compoundA-7, which after deprotection to A-8 can then be coupled as describedfor A-4 to give A-5. It shall be further understood that functionalgroup interconversions can be carried out at any stage of the synthesisprovided that reaction conditions for such conversions are compatiblewith other structural moieties. When compatibility problems areencountered, protecting groups could be used prior to functional groupinterconversion.

Preparation of 7,2 and 8,2 Quinolizinone Framework

Core 7-hydroxy and 8-hydroxy-4-oxo-4H-quinolizine-2-carboxylic acidmethyl esters are prepared using Scheme B.

Hence, for the 7,2-substituted framework compound B-1 such as,2-methyl-5-hydroxy-pyridine is treated with a strong base such as NaH inanhydrous DMSO and then alkylated using, for example, benzyl bromide.The resultant benzyloxy pyridine such as compound B-2 is then oxydisedwith an agent such as 3-chioroperoxybenzoic acid (MCPBA) in a solventsuch as dichioromethane to give the pyridine-N-oxide (compound B-3),which after stirring in hot acetic anhydride (100° C.) provides2-acetoxymethyl-5-benzyloxy pyridine. This compound B-3 is then stirredin a solvent such as methanol and treated with base such as potassiumcarbonate. The resulting alcohol is oxidised with an oxidizing agentsuch as MnO₂ in dry solvent for example dichloromethane in order toobtain compound B-4. Wittig coupling reaction between, for example2-(diethoxyphosphonyl)-succinic acid dimethyl ester, (R′=C₁-C₈ straightchain alkyl) and 5-benzyloxy-pyridine-2-carbaldehyde in a solvent suchas THF and using base like NaH provides the vinolygous adduct (compoundB-5). This compound B-5 can be cyclised in heated solvents, for instancexylenes, in the presence of acid typically p-toluenesulfonic acid inorder to obtain compound B-6. Debenzylation of the resultingquinolizinone in a solvent mixture such as dioxane/methanol In thepresence of palladium over charcoal under hydrogen atmosphere providescompound B-7 such as the core7-hydroxy-4-oxo-4H-quinolizine-2-carboxylic acid methyl ester.

The 8-hydroxy regioisomer is obtained from the same synthetic approachwith the use of 2-methyl-6-hydroxypyridine.

R′=C₁₋₈ straight chain alkyl.

Preparation of 7.2 and 8.2 Substituted Quinolizinone Integrin Inhibitors

7,2 and 8,2 functionalised quinolizinones can be prepared as persynthetic scheme C. Essentially, C-3 is prepared from B-7 by using thesame synthetic approach as described for A-5 from A-2 in scheme A.

It shall be further understood that functional group interconversionscan be carried out at any stage of the synthesis provided that reactionconditions for such conversions are compatible with other structuralmoieties. When compatibility problems are encountered, protecting groupscould be used prior to functional group interconversion.

Preparation of 7 or 8 Aminomethyl Linked Quinolizinones

When C-7 or C-8 carbon linked quinolizinones are desired, these areprepared as per Scheme D. The compound D-1, corresponding to B-7, suchas 7-hydroxy-4-oxo-4H-quinolizine-2-carboxylic acid methyl ester isreacted with an anhydride such as triflic anhydride and the resultingleaving group is displaced by cyanide ion by using for example potassiumcyanide in the presence of paladium. Resulting compound D-2 such as7-cyanoquinolizinone is treated with hydrogen in the presence ofpaladium over charcoal, followed by protection of the amino or couplingwith L—K—J—L′g to give D-2. Compound D-3 such as7-tert-butoxycarbonylamino-methyl-4-oxo-4H-quinolizine-2-carboxylic acidmethyl ester is reacted with base, such as lithium hydroxide and thencoupled with a nucleophillc group comprising X—Y—Z to provide compoundD-4. Compound D-4 results from coupling with L—K—J—L′g, using couplingreagents such as HATU and reactions well known in the art, andaminomethyl intermediates obtained after the removal of protecting groupPg from the C-7 amino substitutent.

Treatment of D-6 with a base such as lithium hydroxide, followed withcoupling reaction to a nucleophilic group comprising —X—Y—Z in thepresence of a coupling reagent such as HATU provides 7-carbon linkedquinolizinones of formula D-5 as described herein.

An alternative route to 7-cyano quinolizinone D-2 is depicted in schemeD. Thus, treatment of 5-Cyano-2-methylpyridine D-01 with an oxydisingagent such as selenium dioxide in a solvent such as dioxane providedpyridine aldehyde D-02 which can be coupled with diethyl ethoxymethylenemalonate under anhydrous basic conditions, obtained for example with NaHin tetrohydrofuran. The resulting adduct is converted directly to D-02by refluxing in an aromatic solvent such as xylenes.

It shall be further understood that functional group interconversionscan be carried out at any stage of the synthesis provided that reactionconditions for such conversions are compatible with other structuralmoieties. When compatibility problems are encountered, protection groupscould be used prior to functional group interconversion.

When C-8 aminomethyl quinolizinones are desired, it will be appreciatedthat the same synthetic route as depicted in Scheme D could be used when4-cyano-2-methylpyridine is used instead of 5-cyano-2-methylpyridinecompound D-01.

Preparation of 7 or 8 Aminomethyl Linked Tetrahydroquinolizinones

C-7 or C-8 carbon linked tetrahydroquinolizinones are prepared accordingto scheme E in which the synthetic route is illustrated for the C-7tetrahydroquinolizinone E-3. Hence, E-3 is prepared from E-1 or E-4using the general scheme process described for converting D-6 or D-4into D-5 from scheme D. E-1 is prepared by treating7-Cyanoquinolizinones D-2 first with excess H2/Pd/C followed withcoupling of 7-aminomethyltetrahydroquinolizinone with a nucleophilecomprising L—K—J—L′g. E-4 is obtained by treating D-2 first with excessH₂/Pd/C, then protecting the 7-aminomethyl group as per the art,followed with basic hydrolysis with a base such as lithium hydroxide andcoupling with a nucleophile comprising —X—Y—Z.

It shall be understood that functional group Interconverslons can becarried out at any stage of the synthesis provided that reactionconditions for such conversions are compatible with other structuralmoeities. When compatibility problems are encountered, protecting groupscould be used prior to functional group interconversion.

Preparation of 8,3 and 8,2-Substituted Quinolizinone Series Bearing anAmino Linker in the L—K—J Group.

As in Scheme F, the compound F-1 is 4-chloro-2-methylpyridine and istreated with a strong non nucleophilic base such as lithiumdiisopropylamide and then coupled with diethyl ethoxymethylene malonate.The resulting adduct F-2 is cyclized in refluxing solvent such asxylenes to provide after basic hydrolysis (eg. LiOH) compound F-3 suchas 8-chloro-4-oxo-4H-quinolizine-3-carboxylic acid. This compound F-3 isthen coupled with nucleophiles incorporating the group —X—Y—Z in thepresence of a coupling reagent such as HATU, typically in a dry solventsuch as DMF. The resulting adduct (compound F-4) can then be coupledwith aminomethylbenzene and treated with base, for example lithiumhydroxide, to afford after debenzylation compound F-5, which can then beused to prepare 8,3-disusbtituted quinolizinone F-6 by coupling F-5 withL—K—J—L′g wherein L′g is a leaving group.

Other analogs are prepared by treating the compound F-4 withnucleophilic groups comprising L—K—J in the presence or absence of basein dry solvent to provide compound F-7. It shall be further understoodthat functional group interconversions can be carried out at any stageof the synthesis provided that reaction conditions for such conversionsare compatible with other structural moieties. When compatibilityproblems are encountered, protecting groups could be used prior tofunctional group interconversion.

8,2-substituted quinolizinones containing an amino linker are preparedby following Scheme F, as described above, provided that5-chloro-2-methyl pyridine is used instead of F-1.

Solid Phase Approach To Synthesize 8, 3. Series Quinolizinones

Such as described in Scheme G, substituted amino propionic acid, G-1, issuitably protected with an amino protecting group such as Fmoc. Theprotected compound, G-2, is anchored to a resin such as Wang resinto.produce G-3. After deprotection of the amino group of G-3, it is thencoupled to a quinolizinone carboxylic acid derivative via standardpeptide coupling techniques to give compound G-4. Substitution of thechlorine group of G-4 employing monoamines or diamines furnished G-5 andG-6, respectively. Compound G-6 can be further elaborated throughreactions of the free terminal amine.

It will be appreciated by those skilled in the art that the compounds orformulas I and II depending on the substituents, may contain one or morechiral centers and thus exist in the form of many different isomers,optical isomers (i.e. enantiomers) and mixtures thereof includingracemic mixtures. All such isomers, enantiomers and mixtures thereofincluding racemic mixtures are included within the scope of theinvention.

One embodiment of the present invention comprises a method or inhibitingan integrin using a compound of formula I and II or any compound orformula disclosed herein that falls within the definition of formula Iand II.

Another embodiment of the present invention comprises a method forinhibiting an α_(v) integrin using a compound of formula I, II, or anycompound or formula disclosed herein that falls within the definition offormula I and II.

Another embodiment of the present invention comprises a method forinhibiting α_(v)β₃ using a compound of formula I, II, or any compound orformula disclosed herein that falls within the definition of formula Iand II.

In yet another embodiment of the present invention comprises a methodfor inhibiting α_(v)⊖₅ using a compound of formula I or II or anycompound or formula disclosed herein that falls within the definition offormula I or II.

Another embodiment of the present invention comprises a method forinhibiting angiogenesis using a compound of formula I or II or anycompound or formula disclosed herein that falls within the definition offormula I or II.

Another embodiment of the present invention comprises a method forpreventing a cell from binding to osteopontin using a compound offormula I or II or any compound or formula disclosed herein that fallswithin the definition of formula I or II.

Another embodiment of the present invention comprises a method forpreventing a cell from binding to fibronectin using a compound offormula I or II or any compound or formula disclosed herein that fallswithin the definition of formula I or II.

Another embodiment of the present invention comprises a method fortreating a tumor using a compound of formula I or II or any compound orformula disclosed herein that falls within the definition of formula Ior II. In another aspect of this invention, the tumor is a solid tumor.Such solid tumors include but are not limited to tumors for cancers thatoriginate in the lung, breast, liver, kidney, brain, pancreas, ovary,uterus, testes, gastrointestinal tract, skin and prostate. The presentis for treatment of mammals such as humans.

Another embodiment of the present invention comprises a method fortreating cancer using a compound of formula I or II or any compound orformula disclosed herein that falls within the definition of formula Ior II.

Another embodiment of the present invention comprises a method fortreating foot in mouth disease using a compound of formula I or II orany compound or formula disclosed herein that falls within thedefinition of formula I or II.

One embodiment of the present invention also provides compositions whichcomprise a pharmaceutically acceptable carrier or adjuvant and aneffective amount of a compound of formula I or II to inhibitangiogenesis and/or tumor growth in a mammal. The proportion of eachcarrier, diluent or adjuvant is determined by the solubility andchemical nature of the compound and the route of administrationaccording to standard pharmaceutical practice.

Therapeutic and prophylactic methods of this embodiment of the inventioncomprise the step of treating patients in a pharmaceutically acceptablemanner with those compounds or compositions. Such compositions may be inthe form of tablets, capsules, caplets, powders, transdermal patches,granules, lozenges, suppositories, reconstitutable powders, or liquidpreparations, such as oral or sterile parenteral solutions orsuspensions.

In order to obtain consistency of administration, it is preferred that acomposition of the invention is in the form or a unit dose. The unitdose presentation forms for oral administration may be tablets andcapsules and may contain conventional excipients. For example, bindingagents, such as acacia, gelatin, sorbitol, or polyvinylpyrrolidone;fillers, such as lactose, sugar, maize-starch, calcium phosphate,sorbitol or glycine; tableting lubricants such as magnesium stearate;disintegrants, such as starch, polyvinylpyrrolidone, sodium starchglycollate or microcrystalline cellulose; or pharmaceutically acceptablewetting agents such as sodium lauryl sulphate.

The compounds may be injected parenterally; this being intramuscularly,intravenously, or subcutaneously. For parenteral administration, thecompound may be used in the form of sterile solutions containing othersolutes, for example, sufficient saline or glucose to make the solutionisotonic. The amount of active ingredient administered parenterally willbe approximately 0.01 to 250 mg/kg/day, preferably about 1 to 10mg/kg/day, more preferably about 0.5 to 30 mg/kg/day, and more mostpreferably about 1-20 mg/kg/day.

The compounds may be administered orally in the form of tablets,capsules, or granules containing suitable excipients such as starch,lactose, white sugar and the like. The compounds may be administeredorally in the form of solutions which may contain coloring and/orflavoring agents. The compounds may also be administered sublingually inthe form of tracheas or lozenges in which each active ingredient ismixed with sugar or corn syrups, flavoring agents and dyes, and thendehydrated sufficiently to make the mixture suitable for pressing intosolid form. The amount of active ingredient administered orally willdepend on bioavailability of the specific compound. The amount of activeingredient administered orally will be approximately 0.01 to 250mg/kg/day, preferably about 1 to 10 mg/kg/day, more preferably about 0.5to 30 mg/kg/day, and more most preferably about 1-20 mg/kg/day.

The solid oral compositions may be prepared by conventional methods ofblending, filling, tableting, or the like. Repeated blending operationsmay be used to distribute the active agent throughout those compositionsemploying large quantities of fillers. Such operations are, of course,conventional in the art. The tablets may be coated according to methodswell known in normal pharmaceutical practice, in particular with anenteric coating.

Oral liquid preparations may be in the form of emulsions, syrups, orelixirs, or may be presented as a dry product for reconstitution withwater or other suitable vehicle before use. Such liquid preparations mayor may not contain conventional additives. For example suspendingagents, such as sorbitol, syrup, methyl cellulose, gelatin,hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, orhydrogenated edible fats; emulsifying agents, such as sorbitanmonooleate or acaci; non-aqueous vehicles (which may include edibleoils), such as almond oil, fractionated coconut oil, oily estersselected from the group consisting of glycerine, propylene glycol,ethylene glycol, and ethyl alcohol; preservatives, for instance methylpara-hydroxybenzoate, ethyl parahydroxybenzoate, n-propylparahydroxybenzoate, or n-butyl parahydroxybenzoate of sorbic acid; and,if desired, conventional flavoring or coloring agents.

For parenteral administration, fluid unit dosage forms may be preparedby utilizing the peptide and a sterile vehicle, and, depending on theconcentration employed, may be either suspended or dissolved in thevehicle. Once in solution, the compound may be injected and filtersterilized before filling a suitable vial or ampoule and subsequentlysealing the carrier or storage package. Adjuvants, such as a localanesthetic, a preservative or a buffering agent, may be dissolved in thevehicle prior to use. Stability of the pharmaceutical composition may beenhanced by freezing the composition after filling the vial and removingthe water under vacuum, (e.g., freeze drying the composition).Parenteral suspensions may be prepared in substantially the same manner,except that the peptide should be suspended in the vehicle rather thanbeing dissolved, and, further, sterilization is not achievable byfiltration. The compound may be sterilized, however, by exposing it toethylene oxide before suspending it in the sterile vehicle. A surfactantor wetting solution may be advantageously included in the composition tofacilitate uniform distribution of the compound.

The pharmaceutical composition of this invention comprise a compound offormula I or II and a pharmaceutically acceptable carrier, diluent oradjuvant. Typically, they contain from about 0.1% to about 99% by weightof active compound, and preferably from about 10% to about 60% by weightdepending on which method of administration is employed.

A pharmaceutically effective amount of compounds of the invention can bedetermined according to one or more of the assays described in detail inthe examples. Under these particular conditions, a compound having suchactivity will exhibit an IC₅₀ of approximately 50 μg/ml or less,preferably 25 μg/ml or less, more preferably 10 μg/ml or less, and mostpreferably less than 1 μg/ml.

Physicians will determine the dosage of the present therapeutic agentswhich will be most suitable. Dosages may vary with the mode ofadministration and the particular compound chosen. In addition, thedosage may vary with the particular patient under treatment. The dosageof the compound used in the treatment will vary, depending on viralload, the weight of the patient, the relative efficacy of the compoundand the judgment of the treating physician. Such therapy may extend forseveral weeks or months, in an intermittent or uninterrupted manner.

To further assist in understanding the present invention, the followingnon-limiting examples are provided.

EXAMPLE 1 Synthesis of the Compounds Compound I:(S)-2-Benzenesulfonylamino-3-{[7-(5-aminopentyloxy)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-propionicAcid TFA Salt

Step A—Preparation of 7-Hydroxy-4-oxo-4H-quinolizine-3-carboxylic AcidEthyl Ester.

To a mixture of 6-methyl-pyridin-3-ol (2.000g, 18.327 mmol) in 160 ml ofanhydrous THF was added at −78° C., 16.1 ml (40.319 mmol) of 2,5 Mn-butyllithium in hexane. The mixture was stirred at−78° C. for 20minutes followed by 1.5 hour at room temperature. The mixture was thencooled down to −78° C. and a solution of diethyl ethoxymethylenemalonate (3.963 g, 18.327 mmol) in 20 ml of the same solvent was addeddropwise. The mixture was stirred at −30° C. for 1 hour, quenched withNH₄Cl sat. and extracted with dichloromethane (3x). The combined organiclayers were washed with water and concentrated. Flash chromatography(dichloromethane to dicholromethane:methanol 95:5) gave 4.760 g (80%yield) of pure alkylated product that was refluxed for 24 hours in 50 mlof xylenes. The mixture was cooled down to room temperature and thedesired product was precipitated and triturated with hexane. Vacuumfiltration afforded 2.230 g (52% yield) of pure desired product as ayellow solid.

Step B—Preparation of7-(5-tert-Butoxycarbonylamino-pentyloxy)-4-oxo-4H-quinolizine-3-carboxylicAcid Ethyl Ester.

A suspension of 7-hydroxy-4-oxo-4H-quinolizine-3-carboxylic acid ethylester in anhydrous DMF was gently heated to activate dissolution. Themixture was then cooled down to room temperature and 10 mg of NaH (60%,0.257 mmol) were added in one portion. The mixture was stirred for 15minutes and a solution of (S-iodopentyl)-carbamic acid tert-butyl ester(154 mg, 514 mmol) in anhydrous DMF was added dropwise. The mixture wasstirred for 24 hours, quenched with water, concentrated and dissolved indichloromethane. The organic layer was washed with water, Na₂CO₃ sat.and dried (MgSO₄) to give 63 mg (70%) of desired product.

Step C—Preparation of7-(5-tert-Butoxycarbonylamino-pentyloxy)-4-oxo-4H-quinolizine-3-carboxylicAcid.

To an ice-cooled mixture of7-(5-tert-butoxycarbonylamlno-pentyloxy)-4-oxo-4H-quinolizine-3-carboxylicacid ethyl ester (15 mg, 0.036 mmol) in THF (1 ml) and water (1 ml) wasadded 3 mg (0.072 mmol) of LiOH in 0.3 ml of water. The mixture wasstirred at room temperature for 24 hours and 3.0 mg of LiOH were addedto complete the reaction. The mixture was concentrated taken with HCl 1Nand extracted (3x) with ethyl acetate. The combined organic layer werewashed with water, dried (Na₂SO₄) to give 10.4 mg (69% yield) of desiredmaterial.

Step D—Preparation of(S)-2-Benzenesulfonylamino-3-{[7-(5-tert-butoxycarbonylaminopentyloxy)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-propionicAcid tert-Butyl Ester.

To a mixture of7-(5-tert-butoxycarbonylamino-pentyloxy)-4-oxo-4H-quinolizine-3-carboxylicacid (22 mg, 0.056 mmol) in 1 ml of anhydrous DMF were added, in thefollowing order, 28 mg (0.073 mmol) of HATU(O-(7-azabenzotriazol-1-yl)-1,3,3-tetramechyluroniumhexafluorophosphate), 17 mg (0.056 mmol) of(S)-2-benzenesulfonylamino-3-amino-propionic acid tert-butyl ester andcollidine (52 μl, 0.392 mmol). The mixture was stirred for 72 hourswhile an addition of 17 mg of(S)-2-benzenesulfonylamino-3-amino-propionic acid tert-butyl ester wasdone after 24 hours and then concentrated. The crude product waspurified by flash chromatography (dichloromethane todichloromethane:acetone; 9:1) to give 3.8 mg of pure desired productalong with mixed fractions. Flash chromatography of the combined mixedfractions (toluene to toluene:ethyl acetate 1:1) gave 8.8 mg of desiredproduct for a total yield of 37%.

Step E—Preparation of(S)-3-{[7-(5-Amino-pentyloxy)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-2-benzenesulfonylamino-propionicAcid Trifluoroacetic Acid Salt. (Compound I).

To a mixture of(S)-2-benzenesulfonylamino-3-{[7-(5-tert-butcxycarbonylamino-pentyloxy)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-propioniicacid tert-butyl ester (8 mg, 0.012 mmol) in 0.5 ml of anhydrousdichloromethane was added 0.5 ml of trifluoroacetic acid. The mixturewas stirred for 2 hours at room temperature and concentrated to affordafter trituration in ether; 6.9 mg (92% yield ) of desired product. Thecompound was characterized with ¹HNMR (400 MHz, CD₃OD) δ: 1.64-1.71 (m,2H), 1.76-1.83 (m, 2H), 1.95-2.02 (m, 2H), 3.00 (broad t, dd, J=7.5 Hz,2H), 3.51-3.56 (dd, J=8.5 Hz, 1H), 3.91-3.96 (dd, J=13.5 and 4.7 Hz,1H), 4.20-4.25 (m, 3H), 7.02 (d, J=8.5 Hz, 1H), 7.27-7.33 (m, 3H),7.59-7.62 (dd, J=9.5 and 2.5 Hz, 3H), 7.80-7.82 (dd, J=7.0 and 1.5 Hz,1H), 7.87 (d, J=8.5 Hz, 1H), 8.34 (d, J=8.5 Hz, 1H), 8.86 (d, J=2.19 Hz,1H).

Compound II:(S)-2-Benzenesulfonylamino-3-{[7-(5-guanidino-pentyloxy)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-propionicAcid Hydrochloride

Step A—Preparation of Compound II From Compound I.

To a mixture of(S)-3-{[7-(5-amino-pentyloxy)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-2-benzenesulfonylamino-propionicacid trifluoroacetic acid salt (compound I)(3.0 mg, 0.005 mmol) in 0.5ml of dimethylformamide and 0.5 ml of water was added 3 μl (0.015 mmol)of diisopropylethylamine and 1.1 mg (0.008 mmol) of1H-pyrazole-1-carboxamidine hydrochloride. The mixture was heated to 60°C. and stirred overnight. Three equivalents of bothdiisopropylethylamine and 1H-pyrazole-1-carboxamidine hydrochloride werethen added in order to complete the reaction. After 6 additional hoursof stirring at 60° C., the mixture was concentrated and the residue waspurified by flash chromatography(EtOH 100% to EtOH:Acetic acid:water;8:1:1) to afford, after treatment with HCl; 2.6 mg (89% yield) ofcompound II which was characterized by ¹HNMR (400 MHz, CD₃CD) δ:1.61-1.75 (m, 4H), 1.95-1.99 (m, 2H), 3.25 (broad t, dd, J=7.0 Hz, 2H),3.50-3.56 (dd, J=13.5 and 8.5 Hz, 1H), 3.90-3.95 (dd, J=13.5 and 4.5 Hz,1H), 4.20-4.25 (m, 3H), 7.03 (d, J=8.5 Hz, 1H), 7.23-7.38 (m, 3H),7.60-7.64 (dd, j=9.5 and 2.5 Hz, 1H), 7.80-7.82 (dd, J=8.0 and 1.5 Hz,1H), 7.88 (d, =9.5 Hz, 1H), 8.34 (d, J=8.5 Hz, 1H), 8.86 (d, J=2.0 Hz,1H).

Compound III:(S)-3-{[7-(3-Amino-propoxy)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-2-benzenesulfonylamino-propionicAcid Trifluoroacetic Acid Salt

Step A—Preparation of7-(3-tert-Butoxycarbonylaminopropoxy)-4-oxo-4H-quinolizine-3-carboxylicAcid Ethyl Ester.

This compound was prepared by using the procedure described in step B ofthe preparation of compound I replacing (5-iodopentyl)-carbamic acidtert-butyl ester by (3-iodopropyl)-carbamic acid tert-butyl ester.

Step B—Preparation of7-(3-tert-Butoxycarbonylaminopropoxy)-4-oxo-4H-quinolizine-3-carboxylicAcid.

This compound was prepared by using the procedure described in step C ofthe preparation of compound I.

Step C—Preparation of(S)-2-Benzenesulfonylamino-3-{[7-(3-tert-Butoxycarbonylaminopropoxy)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-propionicAcid tert-Butyl Ester.

To a mixture of7-(5-tert-butoxycarbonylaminopropoxy)-4-oxo-4H-quinolizine-3-carboxylicacid(25 mg, 0.069 mmol) in 0.5 ml of anhydrous DMF were added, in thefollowing order, 79 mg (0.207 mmol) of HATU(O-(7-azabenzotriazol-1-yl)-1,3,3-tetramethyluroniumhexafluorophosphate), 25 mg (0.083 mmol) of(S)-2-benzenesulfonylamino-3-amino-propionic acid tert-butyl ester andcollidine (64 μl, 0.483 mmol). The mixture was stirred for 24 hours andthe solvent was evaporated. Flash chromatography of the residue (tolueneto toluene:acetone; 4:1) gave 7.6 mg (17% yield) of the desired product.

Step D—Preparation of(S)-3-{[7-(3-Amino-propoxy)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-2-benzenesulfonylamino-propionicAcid Trifluoroacetic Acid Salt (compound III).

Following the procedure described in step E for the preparation ofcompound I, 38 mg (0.059 mmol) of(S)-2-benzenesulfonylamino-3-{[7-(3-tert-butoxycarbonylaminopropoxy)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-propionicacid tert-butyl ester afforded after flash chromatography (ethanol toethanol:ammonium hydroxide:water (8:1:1) and treatment withtrifluoroacetic acid, 12 mg (36% yield) of pure desired product whichwas characterized with ¹HNMR (400 MHz, D₂O) δ: 2.25-2.29 (m, 2H),3.26-3.31 (t, J=6.5 Hz, 1H), 3.42-3.50 (dd, J=10.0 and 13.5 Hz, 1H),3.84-3.90 (dd, J=14.5 and 4.0 Hz, 1H), 4.23-4.26 (m, 3H), 6.90-6.94 (m,2H), 7.04-7.10 (m, 2H), 7.56 (d, J=9.5 Hz, 1H), 7.64 (d, J=7.5 Hz, 2H),7.69-7.75 (m, 1H), 7.91 (d, J=8.5 Hz, 1H).

Compound IV:(S)-2-Benzenesulfonylamino-3-{[7-(3-guanidino-propoxy)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-propionicAcid Hydrochloride

Step A—reparation of Compound IV From Compound III.

Following the procedure described for the preparation of compound II,treatment of compound III afforded compound IV which was characterizedby ¹HNMR (400 MHz, CD₃OD) δ: 2.17-2.23 (m, 2H), 3.47-3.51 (broad t, dd,J=7.0 Hz, 2H), 3.52-3.58 (dd, J=13.5 and 8.5 Hz, 1H), 3.92-3.96 (dd,J=13.5 and 4.5 Hz, 1H), 4.20-4.24 (m, 1H), 4.28-4.31 (broad t, J=6.0 Hz,2H), 6.99 (d, J=8.5 Hz, 1H), 7.26-7.34 (m, 3H), 7.63-7.66 (dd, J=9.5 and2.5 Hz, 1H), 7.80-7.83 (dd, J=7.5 and 1.0 Hz, 2H), 7.87 (d, =9.5 Hz,1H), 8.32 (d, J=8.5 Hz, 1H), 8.85 (d, J=2.5 Hz, 1H).

Compound V:(+/−)(trans)-2-{[7-(3-Amino-propoxy)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-cyclohexanecarboxylicAcid Trifluoroacetic Acid Salt

Step A—Preparation of(+/−)-(trans)-2-{[7-(3-tert-Butoxycarbonylamino-propoxy)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-cyclohexanecarboxylicAcid Methyl Ester.

7-(3-tert-butoxycarbonylaminopropoxy)-4-oxo-4H-quinolizine-3-carboxylicacid (see compound III, step B)(90 mg, 0.248), was dissolved indichloromethane (2 mL) with (+/−)-(trans)-2-amino-cyclohexanecarboxylicacid methyl ester hydrochloride (72 mg, 0.373 mmol) (the commerciallyavailable amino acid (ACROS) was converted to the corresponding methylester via esterification in methanol in the presence oftrimethylsilylchloride followed by evaporation giving the desired methylester which is used without further purification) and 2,4,6-collidine(0.2 ml, 1.8 mmol) while stirring at room temperature. HATU (141 mg,0.38 mmol) was then added to this solution. An extra 1 ml ofdichloromethane was added in order to get a more homogenous reactionmixture then it was left stirring overnight. The reaction mixture wasdiluted with ethyl acetate and washed with a 10% aqueous citric acidsolution then with a sodium bicarbonate solution and then with distilledwater. The organic phase was dried over anhydrous MgSO4 which was thenfiltrated out and the resulting solution was evaporated under reducedpressure leaving a residue which was purified by flash chromatographyeluting with EtOAc: hexanes (1:1) to give 90 mg of a yellow oil.

Step B—Preparation of(+/−)-(trans)-2-{[7-(3-tert-Butoxycarbonylamino-propoxy)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-cyclohexanecarboxylicAcid

(+/−)-(trans)-2-{[7-(3-tert-butoxycarbonylamino-propoxy)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-cyclohexanecarboxylicacid methyl ester (90 mg, 0.179 mmol), was dissolved in 2.0 ml oftetrahydriofuran. To this solution was added sodium hydroxide (approx.20 eq) dissolved In 2.0 ml of distilled water. This solution was stirredovernight at room temperature. The reaction mixture was neutralized withacid to pH 5-7 then extracted with ethyl acetate. The organic layer wasseparated and dried over anhydrous magnesium sulfate. After filtrationand concentration in vacuo the resulting residue was purifiedchromatography on silica gel with ethyl acetate as the eluent to give 60mg of starting material and 27 mg of the desired product.

Step C—Preparation of(+/−)-(trans)-2-{[7-(3-Amino-propoxy)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-cyclohexanecarboxylicAcid Trifluoroacetic Acid Salt (Compound V).

(+/−)-(trans)-2-{[7-(3-tert-butoxycarbonylamino-propoxy)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-cyclohexanecarboxylicacid (21 mg, 0.043 mmol), was dissolved in 1.0 ml of dichloromethane and0.5 ml of trifluoroacetic acid. This solution was stirred overnight atroom temperature. The solvents were evaporated under reduced pressureand the resulting residue was dissolved in a minimum amount of methanol.A large amount of diethyl ether was added to the solution and thedesired product precipitated out of solution, the liquid was separatedand the yellow powder was dried under vacuum. The compound wascharacterized with ¹H NMR (300 MHz, CD3OD) δ: 1.4 (m, 3H), 1.6-1.8 (m,3H), 2.1 (m, 2H), 2.25 (m, 2H), 2.5 (t, 1H), 3.20 (m, 2H), 4.15 (m, 3H),6.95 (dd, 1H), 7.55 (d, 1H), 7.8 (d, 1H), 8.4 (d, 1H) 8.79 (s, 1H).

Compound VI:(S)-2-Benzenesulfonylamino-3-{3-[7-(3-benzyloxycarbonylamino-propoxy)-4-oxo-4H-quinolizine-3-yl]-ureido}-propionicAcid

Step A—Preparation of7-(3-Benzyloxycarbonylamino-propoxy)-4-oxo-4H-quinolizine-3-carboxylicAcid.

This compound was synthesized by following the procedures described inSteps F and G in the preparation of compound XIII however the startingmaterial is 7-hydroxy-4-oxo-4H-quinolizinone-3-carboxylic acid ethylester and 3-iodopropyl)-carbamic acid tert-butyl ester is replaced with(3-iodopropyl)-carbamic acid benzyl ester.

Step B—Preparation of[3-(7-Amino-6-oxo-6H-quinolizine-3-yloxy)-propyl]-carbamic Acid BenzylEster.

To a solution of7-(3-Benzyloxycarbonylamino-propoxy)-4-oxo-4H-quinolizine-3-carboxylicacid (2.2 g, 5.54 mmol) in toluene (100 mL) or aloxane (100 mL) wasadded triethylamine (2.31 mL, 16.62 mmol). The mixture was stirred for15 minutes. Phosphorazidic acid diphenyl ester (2.38 mL, 11.08 mmol) wasadded and the resulting mixture was heated 138° C. (oil bathtemperature) for 15 hours. Water (10 mL) was added and the mixture washeated at 138° C. (oil bath temperature) for an extra 5 hours. Solventswere evaporated to dryness and the residue was purified by flashchromatography 100% ethyl acetate to 10/90 methanol/ethyl acetate.

Step C—Preparation of(S)-2-Benzenesulfonylamino-3-{3-[7-(3-benzyloxycarbonylamino-propoxy)-4-oxo-4H-quinolizin-3-yl]-ureido}-propionicAcid tert-Butyl Ester.

To a solution of[3-(7-amino-6-oxo-6H-quinolizin-3-yloxy)-propyl]-carbamic acid benzylester (35 mg, 0.095 mmol) in tetrahydrofuran (3 mL) at 0° C. was addedphosgene (1 M, 0.10 mL) then the mixture was warmed up to roomtemperature. The reaction mixture was stirred for 3 hours then theexcess phosgene was evaporated using a stream of nitrogen. The mixturewas evaporated to dryness then tetrahydrofuran (6 mL) was added(solution A).

In a separate flask, a suspension(S)-2-benzenesulfonylamino-3-amino-propionic acid tert-butyl ester (33mg, 0.1 mmol) in tetrahydrofuran (6 mL) was treated withdiisopropylethylamine (0.06 mL,). The mixture was stirred 20 minutesthen canulated in solution A . The resulting mixture was stirredovernight then evaporated to dryness and purified by flashchromatography 100% ethyl acetate to give 44 mg of desired compound.

Step D—Preparation of(S)-2-Benzenesulfonylamino-3-{3-[7-(3-benzyloxycarbonylamino-propoxy)-4-oxo-4H-quinolizin-3-yl]-ureido}-propionicAcid (Compound VI).

To a solution of(S)-2-Benzenesulfonylamino-3-{3-[7-(3-benzyloxycarbonylamino-propoxy)-4-oxo-4H-quinolizin-3-yl]-ureido}-propionicacid tert-butyl ester (25 mg, 0.036 mmol) in dichloromethane (3 mL) wasadded TFA(3 ml) at room temperature. The reaction mixture was stirredovernight and then solvents were evaporated under reduced pressure. Theresidue was triturated with ether(2×5 ml) and dried. The resulting solidwas purified by flash chromatography (10% methanol in ethyl acetate) togive 18 mg of compound VI which was characterized by ¹HNMR (300 MHz)(CD3OD) δ: 8.56 (d, 1H, J=7 Hz), 8.40 (s, 1H), 7.92 (m, 2H), 7.42-7.60(m, 4H), 7.25 (m, 5H), 6.91-7.04 (m, 2H), 5.12 (s, 2H), 4.19 (t, 2H),3.63 (m, 1H), 3.50 (m, 2H), 3.20 (m, 2H), 2.02 (m, 2H)

Compound VII:(S)-3-{3-[7-(3-Amino-propoxy)-4-oxo-4H-quinolizin-3-yl]-ureido}-2-Benzenesulfonylamino-propionicAcid

Step A—Preparation of Compound VII From Compound VI.

To a solution of(S)-2-Benzenesulfonylamino-3-{3-[7-(3-benzyloxycarbonylamino-propoxy)-4-oxo-4H-quinolizin-3-yl]-ureido}-propionicacid (compound VI)(10 mg, 0.0156 mmol) in dichloromethane(3 mL) wasadded TMSI (0.04 ml) at room temperature. The reaction mixture wasstirred for 5 hrs then evaporated under reduced pressure. The residuewas triturated with ether(2×5 ml) and dried to yield compound VII (6 mg)which was characterized by ¹HNMR (300 MHz) (CD₃OD) δ: 8.56 (d, 1H, J=7Hz), 8.42 (s, 1H), 7.96 (m, 2H), 7.66 (d, 1H, 6 Hz), 7.45 (m, 3H),6.91-717 (m, 2H), 4.22 (t, 2H), 4.05 (m, 2H), 3.63 (m, 1H), 3.23 (m,2H), 222 (m, 2H).

Compound VIII:(+/−)-3-{3-[7-(3-Guanidino-propoxy)-4-oxo-4H-quinolizin-3-yl]-ureido}-3-pyridin-3-yl-propionicAcid

Step A—Preparation of(+/−)-3-{3-[7-(3-Benzyloxycarbonylamino-propoxy)-4-oxo-4H-quinolizin-3-yl]-ureido}-3-pyridin-3-yl-propionicAcid Ethyl Ester.

To a solution of[3-(7-amino-6-oxo-6H-quinolizin-3-yloxy)-propyl]-carbamic acid benzylester (710 mg, 0.19 mmol) in tetrahydrofuaran (6 mL) at 0° C. was addedphosgene (1M, 0.38 mL, 0.38 mmol). The mixture was then warmed to roomand was stirred for 3 hours. Excess phosgene was evaporated using astream of nitrogen and the remaining solvent was pumped out. The residuewas redissolved in tetrahydrofuran (6 mL)(Solution A).

To a suspension of 3-Amino-3-pyridin-3-yl-propionic acid ethyl esterbis-hydrochloric acid salt (71.2 mg, 0.285 mmol) in tetrahydrofuran (6mL) was added diisopropylethylamine (0.165 mL, 0.95 mmol). The mixturewas stirred 20 minutes and was then canulated in solution A.

The resulting mixture was stirred overnight then evaporated to drynessand purified by flash chromatography eluting with 0-10% methanol inethyl acetate to give 69 mg of the title compound.

Step B—Preparation of(+/−)-3-{3-[7-(3-Amino-propoxy)-4-oxo-4H-quinolizin-3-yl]-ureido}-3-pyridin-3-yl-propionicAcid Ethyl Ester.

To a solution of(+/−)-3-{3-[7-(3-Benzyloxycarbonylamino-propoxy)-4-oxo-4H-quinolizin-3-yl]-ureido}-3-pyridin-3-yl-propionicacid ethyl ester (32.7 mg, 0.056 mmol) in acetonitrile (4 mL) was addediodotrimethylsilane (0.012 mg, 0.084 mmol). The mixture was stirred for1.5 hours, evaporated to dryness and the residue was triturated in ether(2X) and in dichloromethane (1X). The solid was dried under vacuum andused as such for one next step.

Step C—Preparation of(+/−)-3-{3-[7-(3-Bis-BOC-guanidino-propoxy)-4-oxo-4H-quinolizin-3-yl]-ureido}-3-pyridin-3-yl-propionicAcid Ethyl Ester.

To a solution of(+/−)-3-{3-[7-(3-amino-propoxy)-4-oxo-4H-quinolizin-3-yl]-ureido}-3-pyridin-3-yl-propionicacid ethyl ester (28 mg, 0.05 mmol) in dimethylformamide (4 mL) wasadded diisopropylethylamine (0.015 mL, 0.110 mmol) and(tert-Butoxycarbonylimino-pyrazol-1-yl-methyl)-carbamic acid tert-butylester (23 mg, 0.075 mmol). The mixture was heated to 60° C. and stirredovernight. The solution was evaporated to dryness and the residue wastriturated in ether and dried and was used as such for the next step.

Step D—Preparation of(+/−)-3-{3-[7-(3-Bis-BOC-guanidino-propoxy)-4-oxo-4H-quinolizin-3-yl]-ureido}-3-pyridin-3-yl-propionicAcid.

To a solution of(+/−)-3-{3-[7-(3-Bis-BOC-guanidino-propoxy)-4-oxo-4H-quinolizin-3-yl]-ureido}-3-pyridin-3-yl-propionicacid ethyl ester (28 mg, 0.04 mmol) in THF/H₂O (1:1, 2 mL) was addedLiOH (19 mg, 0.80 mmol). The mixture was stirred for 5 hrs at roomtemperature. The solution was neutralized with acetic acid thenextracted with EtOAc (5 ml). Solvent was then evaporated to dryness. Thecrude was used has such for the next step.

Step E—Preparation of(+/−)-3-{3-[7-(3-Guanidino-propoxy)-4-oxo-4H-quinolizin-3-yl]-ureido}-3-pyridin-3-yl-propionicAcid (Compound VIII)

A solution of(+/−)-3-{3-[7-(3-Bis-BOC-guanidino-propoxy)-4-oxo-4H-quinolizin-3-yl]-ureido}-3-pyridin-3-yl-propionicacid (20 mg, 0.029 mmol) in CH₂Cl₂/TFA (1:1, 2 mL) was stirred overnightat room temperature. The solution was evaporated to dryness. The crudewas purified on silica gel chromatography using EtOH:H₂O:NH₄OH (8:1:1)as eluent yielding 20 mg of pure compound VIII in 83% yield which wascharacterized by ¹HNMR (300 MHz) (CD₃OD) δ: 8.60 (s, 1H), 8.44 (m, 3H),7.92 (d, 1H) 7.55 (d, 1H) 7.41 (d, 1H), 7.19 (d, 1H), 6.93 (d, 1H), 5.30(m, 1H), 4.11 ((m, 2H) 3. 66 (m, 2H), 2.73 (m, 2H), 2.11 (m, 2H)

Compound IX:(S)-2-Benzenesulfonylamino-3-{3-[7-(3-guanidino-propoxy)-4-oxo-4H-quinolizin-3-yl]-ureido}-propionicAcid Trifluoroacetate Salt

Step A—Preparation of(S)-3-{3-[7-(3-Amino-propoxy)-4-oxo-4H-quinolizin-3-yl]-ureido}-2-benzenesulfonylamino-propionicAcid tert-Butyl Ester.

To a solution of(S)-2-Benzenesulfonylamino-3-{3-[7-(3-benzyloxycarbonylamino-propoxy)-4-oxo-4H-quinolizin-3-yl]-ureido}-propionicacid tert-butyl ester(25 mg, 0.0360 mmol) in acetonitrile (5 mL) at 25°C. was added TMSI (0.015 mL,). The reaction mixture was stirred for 2hours then the solvent was evaporated under reduced pressure. Theresidue was used in the next step without any further purification.

Step B—Preparation of(S)-2-Benzenesulfonylamino-3-{3-[7-(3-guanidino-propoxy)-4-oxo-4H-quinolizin-3-yl]-ureido}-propionicAcid tert-Butyl Ester.

To a solution of(S)-3-{3-[7-(3-amino-propoxy)-4-oxo-4H-quinolizin-3-yl]-ureido}-2-benzenesulfonylamino-propionicacid tert-butyl ester (47.6 mg, 0.0829 mmol) in dimethylformamide (1 mL)and water (1 mL) was added diisopropylethylamine (0.032 mL, 0.182 mmol)and pyrazole-1-carboxamidine hydrochloride (18 mg, 0.124 mmol). Themixture was heated to 60° C. for 5 hrs. The solution was evaporated todryness then triturated in ether (2X). The crude was used as such forthe next step.

Step C—Preparation of(S)-2-Benzenesulfonylamino-3-{3-[7-(3-guanidino-propoxy)-4-oxo-4H-quinolizin-3-yl]-ureido}-propionicAcid; Trifluoro-acetate Salt (Compound IX).

To a suspension(S)-2-benzenesulfonylamino-3-{3-[7-(3-guanidino-propoxy)-4-oxo-4H-quinolizin-3-yl]-ureido}-propionicacid tert-butyl ester (30 mg, 0.049 mmol) in dichloromethane (4 mL) wasadded trifluoroacetic acid (6 mL). The mixture was stirred overnight,evaporated to dryness and triturated in ether (3X) and hexane (1X).Compound IX was purified by preparative HPLC using 1:1 MeCN:H2O aseluent and characterized by ¹H NMR (400 MHz) (CD3OD) d: 8.51 (d, 1H,J=8.5 Hz), 8.45 (s, 1H), 7.98-7.85 (m, 2H), 7.63 (d, 1H, J=9 Hz),7.49-7.47 (m, 3H), 7.10 (d, 1H, J=9 Hz), 6.98 (d, 1H, J=8.5 Hz), 4.20(t, 2H, J=5.5 Hz), 4.03-4.01 (m, 1H), 3.65-3.62 (m, 1H), 3.49-3.42 (m,3H), 2.20-2.14 (m, 2H)

Compound X:(+/−)-3-{7-[3-(3-Benzyl-ureido)-propoxy]-4-oxo-4H-quinolizine-3-carbonyl}-amino)-3-phenyl-propionicAcid

Step A—Preparation of(+/−)-3-{[7-(3-tert-Butoxycarbonylamino-propoxy)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-3-phenyl-propionicAcid Ethyl Ester.

To a mixture of7-(3-tert-butoxycarbonylamino-propoxy)-4-oxo-4H-quinolizine-3-carboxylicacid (28 mg, 0.077 mmol) in anhydrous DMF (0.5 ml) was added HATU(O-(7-azabenzotriazol-1-yl)-1,3,3-tetramethyluroniumhexafluorophosphate) (88 mg, 0.232 mmol),(+/−)-3-amino-3-phenyl-propionic acid ethyl ester (15 mg, 0.077 mmol)and collidine (71 μl, 0.539 mmol). The mixture was stirred for 72 hoursand the solvent was evaporated in vacuo. Flash chromatography(dichloromethane to dichloromethane:acetone:acetic acid; 95:5:1) of theresidue gave 27.0 mg (68% yield) of the desired product.

Step B—Preparation of(+/−)-3-({7-[3-(3-Benzyl-ureido)-propoxy]-4-oxo-4H-quinolizine-3-carbonyl}-amino)-3-phenyl-propionicAcid Ethyl Ester.

To a mixture of(+/−)-3-{[7-(3-tert-butoxycarbonylamino-propoxy)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-3-phenyl-propionicacid ethyl ester (100 mg, 0.1813 mmol) in anhydrous dichloromethane (3.0ml) was added 1.0 ml of trifluoroacetic acid. The mixture was stirredfor 30 minutes, concentrated and the residue was triturated in ether,filtered off, suspended in dichloromethane and washed with NaHCO₃ sat.,dried with Na₂SO₄ and concentrated. The residue was dissolved inanhydrous acetonitrile (0.3 ml) and 18 μl of benzyl isocyanate wasadded. The mixture was stirred at room temperature for 30 minutes,quenched with water and extracted with dichloromethane. The combinedorganic layers were washed with water and dried (Na₂SO₄). Flashchromatography of the crude (0-10% methanol in dichloromethane) gave 83mg (99% yield) of desired product.

Step C—Preparation of(+/−)-3-({7-[3-(3-Benzyl-ureido)-propoxy]-4-oxo-4H-quinolizine-3-carbonyl}-amino)-3-phenyl-propionicAcid (Compound X).

To a mixture of(+/−)-3-({7-[3-(3-benzyl-ureido)-propoxy]-4oxo-4H-quinolizine-3-carbonyl}-amino)-3-phenyl-propionicacid ethyl ester(29 mg, 0.0508 mmol) in acetonitrile (0.4 ml) and water(0.4 ml) was added 8.5 mg of monohydrated LiOH. The mixture was stirredfor 3 hours, acidified to pH 1-2 with KHSO₄ sat., and extracted withethyl acetate. The combined organic layers were washed with water anddried (Na₂SO₄). Flash chromatography (dichloromethane:methanol; 9:1)gave 17.7 mg (64% yield) of desired product which was characterized by¹HNMR (300 MHz, DMSC-d₆) δ: 1.73-2.26 (m, 2H), 2.52-2.57 (m, 2H),3.20-3.22 (m, 2H), 4.17-4.19 (m, 4H), 5.44 (m, 1H), 6.45 (m, 1H), 6.67(m, 1H), 7.06-7.28 (m, 8H), 7.34-7.37 (m, 2H), 7.68 (d, J=8.5 Hz, 1H),7.95 (d, 9.5 Hz, 1H), 8.31-8.34 (d, J-8.5 Hz, 1H), 8.74 (broad s, 1H).

Compound XI:(+/−)-3-{[7-(3-Benzyloxycarbonylamino-propoxy)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-3-phenyl-propionicAcid

Step A—Preparation of(+/−)-3-{[7-(3-Benzyloxycarbonylamino-propoxy)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-3-phenyl-propionicAcid Ethyl Ester.

(+/−)-3-{[7-(3-tert-butoxycarbonylamino-propoxy)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-3-phenyl-propionicacid ethyl ester (42 mg, 0.084 mmol) was mixed with TFA/CH₂Cl₂ (1:1,8ml) at room temperature and the mixture was stirred overnight. Solventswere then evaporated and the residue was triturated with ether (2×15ml). To the resulting solid was added a solution of sodium carbonate 18mg (0,17 mmol) in dioxane (10 ml). The reaction was cooled to 0° C. andCBZCl was added dropwise during a period of 10 min. The reaction wasthen stirred for 4 hours. Insolubles were removed by filtration and thesolvent was evaporated under high vacuum. Purification of the residue onsilica gel using 70% EtOAc in hexane afforded pure(+/−)-3-{[7-(3-Benzyloxycarbonylamino-propoxy)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-3-phenyl-propionicacid ethyl ester (75%, 0.062 mmol).

Step B—Preparation of(+/−)-3-{[7-(3-Benzyloxycarbonylamino-propoxy)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-3-phenyl-propionicAcid (Compound XI).

The compound from step A was hydrolyzed using LiOH/THF according to theprocedure described in the preparation of compound I (step C). Thisafforded the expected product (18 mg, 65% yield) which was characterizedby ¹HNMR (300 MHz, CD₃OD) δ: 8.58 (s, 1H), 8.20 (d, 1H), 7.57 (d, 1H),7.20-7.49 (m 11H), 6.78 (d, 1H), 5.61 (t, 1H), 5.05 (s, 2H), 4.09 (t,2H), 3.34 (m, 3H), 2.96 (m, 2H) 2.00 (t, 2H).

Compound XII:(S)-2-Benzenesulfonylamino-3-({7-[3-(3-methyl-ureido)-propoxy]-4-oxo-4H-quinolizine-2-carbonyl}-amino)-propionicAcid

Step A—Preparation of3-{[7-(3-Amino-propoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-2-benzenesulfonylamino-propionicAcid tert-Butyl Ester.

To a mixture of(S)-2-benzenesulfonylamino-3-{[7-(3-tert-butoxycarbonylamino-propoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionicacid tert-butyl ester (for the preparation of this product, see compoundXIV: step A) (100.0 mg, 0.155 mmol) in anhydrous THF (0.75 ml) was addedtrifluoroacetic acid (0.75 ml). The mixture was stirred under nitrogenatmosphere for 48 hours, concentrated and triturated in ether.Filtration gave 91 mg (89% yield) of a yellow precipitate (containingca. 5% of starting material).

Step B—Preparation of(S)-2-Benzenesulfonylamino-3-({7-[3-(3-methyl-ureido)-propoxy]-4-oxo-4H-quinolizine-2-carbonyl}-amino)-propionicAcid tert-Butyl Ester.

To a mixture of(S)-3-{[7-(3-amino-propoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-2-benzenesulfonylamino-propionicacid tert-butyl ester (10.0 mg, 0.015 mmol) in anhydrous acetonitrile(0.5 ml) were added triethylamine (4 μl, 0.030 mmol) and methylisocyanate (1 μl, 0.015 mmol). The mixture was stirred for 5 minutes at0° C. and 30 minutes at room temperature, quenched with water andextracted with dichloromethane (3x). The combined organic layers weredried (MgSC₄) and concentrated to give 4.1 mg (81% yield) of desiredproduct.

Step C—Preparation of(S)-2-Benzenesulfonylamino-3-({7-[3-(3-methyl-ureido)-propoxy]-4-oxo-4H-quinolizine-2-carbonyl}-amino)-propionicAcid (Compound XII).

To a mixture of(S)-2-Benzenesulfonylamino-3-{7-[3-(3-methyl-ureido)-propoxy]-4-oxo-4H-quinolizine-2-carbonyl}-amino)-propionicacid tert-butyl ester (7.0 mg, 0.012 mmol) in anhydrous dichloromethane(0.5 ml) was added trifluoroacetic acid (0.5 ml). The mixture wasstirred for 5 hours at room temperature, concentrated and triturated inether to give 5.9 mg of a crude residue. Flash chromatography(dichloromethane to dichloromethane:methanol:ethyl acetate; 70:29:1)gave 3.6 mg (56% yield) of desired product. ¹HNMR (400 MHz, D₂O)2.04-2.07 (m, 2H), 2.64 (s, 3H), 3.31-3.35 (m, 2H), 3.38-3.44 (m, 1H)3.70-3.75 (m, 1H), 3.96-3.99 (m, 1H), 4.17-4.20 (m; 2H), 6.57 (s, 1H),7.08 (s, 1H), 7.11-7.15 (m, 1H) 7.24-7.28 (m, 2H), 7.46-7.48 (m, 1H),7.71-7.80 (m, 3H), 7.46 (s, 1H)

Compound XIII: 7-(3-Amino-propoxy)-4-oxo-4H-quinolizine-2-carboxylicAcid Trifluoroacetic Acid Salt

Step A—Preparation of 5-Benzyloxy-2-methyl-pyridine.

A suspension of NaH 60% (1.210 g) in anhydrous DMSO (40 ml) was stirredat 100° C. for 20 minutes (gas liberation), cooled to room temperature6-methyl-pyridin-3-ol (3.000 g) was added in one portion. The resultingmixture was stirred at room temperature for 20 minutes and benzylbromide (3.60 ml) was added. The mixture was stirred for 78 hours,dropped in NH₄Cl sat. and extracted with ether (3×). The combinedorganic layers were washed with water, brine and dried (MgSO₄). Flashchromatography (ether) of the crude gave 5.131 g (94% yield) of puredesired product as a colorless oil.

Step B—Preparation of Acetic Acid 5-Benzyloxy-pyridin-2-ylmethyl Ester.

To an ice-cooled solution of 5-benzyloxy-2-methyl-pyridine (1.000 g,5.018 mmol) in anhydrous dichloromethane (50 ml) was added3-chloroperoxybenzoic acid (MCPBA, 953 mg, 5.520 mmol). The mixture wasstirred for 60 minutes at 0° C. (while 2 extra additions of 514 mg and500 mg of MCPSA were done after 30 and 60 minutes respectively) and 30minutes at room temperature, dropped in NaHCO₃ sat, stirred for 15minutes and extracted with dichloromethane (2x). The combined organiclayers were washed with water and dried (MgSO4). Flash chromatography(ethyl acetate to dichloromethane:methanol; 95:5) of the crude gave1.034 g (96% yield) of the N-oxide which was treated with anhydrousacetic anhydride (5 ml). The mixture was stirred at 100° C. for 30minutes in a preheated oil bath, cooled down to room temperature,concentrated and the residue was flash chromatographed (0-5% acetone indichloromethane) to give 879 mg (74% yield) of pure desired product.

Step C—Preparation of 5-Benzyloxy-pyridine-2-carbaldehyde.

To a mixture of acetic acid 5-benzyloxy-pyridin-2-ylmethyl ester (14.764g, 57.381 mmol) in methanol (200 ml) was added potassium carbonate (793mg, 5.738 mmol). The resulting mixture was stirred overnight (18 hours)neutralized with acetic acid, concentrated, redissolved indichioromethane, washed with NaHCO₃ sat., dried (MgSO₄) and concentratedto afford 11.411 g of the free alcohol of which (3.000 g, 13.936mmol)were dissolved in anhydrous dichloromethane (140 ml) under nitrogenatmosphere. MnO₂ (11.357 g, 130.936 mmol)was added and the mixture wasstirred at room temperature for 24 hours (while 6 g additional of MnO₂were added after 18 hours of stirring). The reaction mixture was thenfiltered through a pad of SiO₂ eluting with 20% acetone indichloromethane) to afford 2.342 g of pure aldehyde as a white solid.

Step D—Preparation of 7-Benzyloxy-4-oxo-4H-quinolizine-2-carboxylic AcidMethyl Ester.

To a solution of 2-(Diethoxy-phosphoryl)-succinic acid dimethyl-ester(1.6554 g, 5.861 mmol) in anhydrous THF (40 ml) at 0° C. was added inone portion NaH 60% (235 mg, 5,861 mmol). The mixture was stirred for 20minutes at room temperature (until end of gas evolution) and cooled downto 0° C. A solution of 5-benzyloxy-pyridine-2-carbaldehyde (1.000 g,4.689 mmol) in the same solvent (10 ml) was added dropwise. The mixturewas stirred at room temperature for 3 hours, quenched with water andextracted with ethyl acetate (3x). The combined organic layers werewashed with brine and dried (MgSO₄). Flash chromatography (hexane tohexane:ethyl acetate; 1:1 to dichloromethane:ethyl acetate; 9:1) of thecrude gave 946 mg of the desired product which was dissolved in xylene(30 mL). A catalytic amount of PTSA (52 mg) was then added and themixture was stirred at 150° C. for 2 hours, cooled to room temperatureand purified through a short silica gel column eluting with 0-20%acetone in dichloromethane yielding 801 mg (94% yield) of desiredproduct.

Step E—Preparation of 7-Hydroxy-4-oxo-4H-quinolizine-2-carboxylic AcidMethyl Ester.

A mixture of 7-benzyloxy-4-oxo-4H-quinolizine-2-carboxylic acid methylester (3.900 g, 12.608 mmol) in dioxane (100 ml) and methanol (12 ml) inthe presence of Pd/C 10%(390 mg) was stirred under an atmosphere ofhydrogen for 2 hours, diluted with methanol, filtered through celite andconcentrated to give 2.282 g (83% yield) of desired product as a yellowsolid.

Step F—Preparation of7-(3-tert-Butoxycarbonylamino-propoxy)-4-oxo-4H-quinolizine-2-carboxylicAcid Methyl Ester.

To a mixture of 7-hydroxy-4-oxo-4H-quinolizine-2-carboxylic acid methylester (60 mg, 0.274 mmol) in anhydrous DMF (6 ml) was added cesiumcarbonate (107 mg, 0.328 mmol) followed by (3-iodopropyl)-carbamic acidtert-butyl ester (94 mg, 0.328 mmol). The mixture was stirred for 18hours under nitrogen atmosphere, diluted with dichloromethane, washedwith NH₄Cl sat. (3x), water and dried (MgSO₄). Flash chromatography ofthe crude (dichloromethane to ethyl acetate) gave 46 mg (47% yield) ofpure desired product as a yellow solid.

Step G—Preparation of7-(3-tert-Butoxycarbonylamino-propoxy)-4-oxo-4H-quinolizine-2-carboxylicAcid.

To a mixture of7-(3-tert-butoxycarbonylamino-propoxy)-4-oxo-4H-quinolizine-2-carboxylicacid methyl ester (44 mg, 0.117 mmol) in THF (0.5 ml) and water (0.5 ml)was added in one portion LiOH monohydrate (12 mg, 0.292 mmol). Themixture was stirred at room temperature for 30 minutes, acidified with1N HCl (a few drops) and extracted with ethyl acetate (3x). The combinedorganic layers were washed with brine and dried (MgSO₄) to give 36.6 mg(87% yield) of the desired product as a yellow solid.

Step H—Preparation of7-(3-Amino-propoxy)-4-oxo-4H-quinolizine-2-carboxylic AcidTrifluoroacetic Acid Salt (Compound XIII).

To a mixture of7-(3-tert-butoxycarbonylamino-propoxy)-4-oxo-4H-quinolizine-2-carboxylicacid (18 mg, 0.050 mmol) in anhydrous dichloromethane (1 ml) undernitrogen atmosphere was added trifluoroacetic acid (1 ml). The mixturewas stirred for 2 hours at room temperature, concentrated and trituratedwith ether to give 17.3 mg (92% yield) of desired compound as a yellowsolid which was characterized by ¹HNMR (300 MHz, CD₃OD) δ: 2.22-2.29 (m,2H), 3.20-3.23 (m, 2H), 4.28-4.31 (m, 2H) 7.09 (d, J=1.5 Hz, 1H),7.46-7.49 (dd, J=9.5 and 2.5 Hz, 1H) 7.52 (s, 1H), 7.90 (d, J=9.5 Hz,1H), 8.71 (s, 1H).

Compound XIV:(S)-3-{[7-(3-Amino-propoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-2-benzenesulfonylamino-propionicAcid Trifluoroacetic Acid Salt

Step A—Preparation of(S)-2-Benzenesulfonylamino-3-{[7-(3-tert-butoxycarbonylamino-propoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionicAcid tert-Butyl Ester.

To a mixture of7-(3-tert-butoxycarbonylamino-propoxy)-4-oxo-4H-quinolizine-2-carboxylicacid (36 mg, 0.99 mmol) in anhydrous DMF was added HATU, followed by(S)-3-amino-2-benzenesulfonylamino-propionic acid tert-butyl esterhydrochloride (40 mg, 0.119 mmol) and collidine (91 μl, 0.693 mmol). Themixture was stirred for 1 hour under nitrogen atmosphere at roomtemperature and then concentrated. The oily residue was dissolved inethyl acetate, washed with 10% aqueous citric aced, NaHCO₃ sat., brineand dried (MgSO₄) Filtration through a short silica gel column elutingwith ethyl acetate gave 56 mg (88% yield) of pure desired product asyellow solid.

Step B—Preparation of(S)-3-{[7-(3-Amino-propoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-2-benzenesulfonylamino-propionicAcid Trifluoroacetic Acid Salt (Compound XIV).

To a mixture of(S)-2-benzenesulfonylamino-3-{[7-(3-tert-butoxycarbonylamino-propoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionicacid tert-butyl ester (52 mg, 0.802 mmol) in anhydrous dichloromethane(1 ml) was added the trifluoroacetic acid (0.5 ml). The mixture wasstirred for 2 hours, concentrated and triturated in ether. The yellowsolid was lyophilized in water to give 39.2 mg (81% yield) of desiredproduct as yellow powder which was characterized by ¹HNMR (400 MHz, D₂O)δ: 2.03-2.19 (m, 2H), 3.14-3.22 (m, 2H), 3.34-3.40 (dd, J=14.0 and 10.0Hz, 1H), 3.64-3.69 (dd, J=14.0 and 4.5 Hz, 1H), 4.06-4.18 (m, 3H), 6.39(d, J=2.0 Hz, 1H), 6.87 (d, J=1.5 Hz, 1H), 7.04-7.08 (m, 1H), 7.13-7.22(m, 2H), 7.25-7.30 (dd, J=9.5 and 2.5 Hz, 1H), 7.54-7.67 (m, 3H), 8.24(d , J=2.0 Hz, 1H). HPLC (250 nm) 90% acetonitrile 10% water (100%pure), Mass.: 489.2 M-113 (TFA).

Compound XV:(S)-2-Benzenesulfonylamino-3-{[7-(3-guanidino-propoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionicAcid Hydrochloride

Step A—Preparation of Compound XV From Compound XIV.

A mixture of(S)-3-{[7-(3-amino-propoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-2-benzenesulfonylamino-propionicacid trifluoroacecic acid salt (compound XIV)(15 mg, 0.025 mmol),diisopropylethylamine (13 μl, 0.075 mmol) and1H-pyrazole-1-carboxamidine hydrochloride (6 mg, 0.038 mmol) in DMF (0.5ml) and water (0.5 ml) was stirred at 60° C. for 7 hours. It was thenconcentrated and the residue was flash chromatographed(ethanol:NH₄OH:water; 8:1:1) and lyophilized in a (1:1) mixture of 0.1NHCl and water to afford 11.4 mg of pure desired product as a yellowsolid which was characterized by ¹HNMR (400 MHz, CD₃OD) δ: 2.14-2.21 (m,2H), 3.44-3.48 (m,2H), 3.49-3.54 (dd, J=13.5 and 9.0 Hz, 1H), 3.77-3.82(dd, J=13.5 and 5.0 Hz, 1H), 4.23-4.28 (m, 3H), 6.94 (d, J=1.5 Hz, 1H),7.37 (s, 1H), 7.43-7.56 (m, 4H), 7.85-7.86 (m, 2H), 7.91 (d, J=9.5 Hz,1H), 8.7 (s, 1H).

Compound XVI:3-{[7-(3-Amino-propoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionicAcid Trifluoroacetic Acid Salt

Step A—Preparation of3-{[7-(3-tert-Butoxycarbonylamino-propoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionicAcid tert-Butyl Ester

This compound was prepared using the procedure described in thepreparation of compound XIV (step A) replacing(S)-3-amino-2-benzenesulfonylamino-propionic acid tert-butyl esterhydrochloride by 3-amino propionic acid tert-butyl ester.

Step B—Preparation of3-{[7-(3-Amino-propoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionicAcid Trifluoroacetic Acid Salt (Compound XVI).

This compound was prepared in 92% yield using the procedure described inthe preparation of compound XIV (step B) as a yellow solid which wascharacterized by ¹HNMR (400 MHz, CD₃OD) δ: 2.15-2.28 (m, 2H), 2.65-2.70(m, 2H), 3.13-3.23 (m, 2H), 3.64-3.75 (m, 2H), 4.26-4.23 (m, 2H), 6.89(d, J=1.5 Hz, 1H), 7.30-7.31 (d, J=1.5 Hz, 1H), 7.46-7.49 (dd, J=9.5 and2.5 Hz, 1H), 7.84 (d, J=9.5 Hz, 1H), 8.67 (d, J=2.0 Hz, 1H).

Compound XVII:(S)-3-{[7-(4-Amino-butoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-2-benzenesulfonylamino-propionicAcid Trifluoroacetic Acid Salt

Step A—Preparation of7-(4-tert-butoxycarbonylamino-butoxy)-4-oxo-4H-quinolizine-2-carboxylicAcid Methyl Ester.

This compound was synthesized from7-hydroxy-4-oxo-4H-quinolizine-2-carboxylic acid methyl ester asdescribed in step F of the preparation of compound XIII replacing(3-iodopropyl)-carbamic acid zert-butyl ester by (4-iodobutyl)-carbamicacid tert-butyl ester.

Step B—Preparation of7-(4-tert-Butoxycarbonylamino-butoxy)-4-oxo-4H-quinolizine-2-carboxylicAcid.

This compound was synthesized from7-(4-tert-butoxycarbonylamino-butoxy)-4-oxo-4H-quinolizine-2-carboxylicacid methyl ester using the procedure described in step G of thepreparation of compound XIII.

Step C—Preparation of(S)-2-Benzenesulfonylamino-3-{[7-(4-tert-butoxycarbonylamino-butoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionicAcid tert-butyl Ester.

This compound was prepared from7-(4-tert-butoxycarbonylamino-butoxy)-4-oxo-4H-quinolizine-2-carboxylicacid using the procedure described in step A of the preparation ofcompound XIV.

Step D—Preparation of(S)-3-{[7-(4-Amino-butoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-2-benzenesulfonylamino-propionicAcid Trifluoroacetic Acid Salt (Compound XVII).

This compound was prepared from(S)-2-benzenesulfonylamino-3-{[7-(4-tert-butoxycarbonylamino-butoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionicacid tert-butyl ester in 82% yield of pure desired product as a yellowsolid using the procedure described in step B of the preparation ofcompound XIV. The compound was characterized with by ¹HNMR (400 MHz,CD₃OD) δ: 1.85-2.03 (m, 4H), 3.04-3.14 (m, 2H), 3.45-3.56 (dd, J=13.5and 9.0 Hz, 1H), 3.77-3.81 (dd, 13.5 and 5.0 Hz, 1H), 4.21-4.26 (m, 3H),6.88 (d, J=1.5 Hz, 1H), 7.29 (s, 1H), 7.44-7.56 (m, 4H), 7.80-7.87 (m,3H), 8.69 (s, 1H). ¹³CNMR (100 MHz, CD₃OD) δ: 23.07, 24.55, 38.15,41.09, 54.34, 67.15, 102.55, 103.70, 106.45, 125.40, 125.69, 126.42,127.73, 131.26, 138.17, 139.76, 140.04, 150.82, 157.01, 165.95, 170.40.

Compound XVIII:(S)-2-Benzenesulfonylamino-3-{[7-(4-guanidino-butoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionicAcid Hydrochloride

Step A—Preparation of compound XVIII from compound XVII.

Following the procedure described for the preparation of compound XVfrom compound XIV, compound XVII (35 mg, 0.057 mmol) afforded 32 mg (97%yield) of pure compound XVIII as a yellow solid which was characterizedby 1H NMR (400 MHz, CD₃OD) δ: 1.83-1.86 (m, 2H), 1.88-2.00 (m, 2H),3.50-3.56 (dd, J=13.5 and 9.0 Hz, 1H), 3.77-3.81 (dd, J=13.5 and 5.0 Hz,1H), 4.21-4.27 (m, 3H), 6.90 (s, 1H), 7.33 (s, 1H), 7.45-7.53 (m, 4H),7.84-7.90 (m, 3H), 8.69 (s, 1H).

Compound XIX:(S)-3-{[7-(2-Amino-ethoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-2-benzenesulfonylamino-propionicAcid Trifluoroacetic Acid Salt

Step A—Preparation of7-(2-tert-Butoxycarbonylamino-ethoxy)-4-oxo-4H-quinolizine-2-carboxylicAcid Methyl Ester.

This compound was synthesized from7-hydroxy-4-oxo-4H-quinolizine-2-carboxylic acid methyl ester asdescribed in step F of the preparation of compound XIII replacing(3-iodoprcpyl)-carbamic acid tert-butyl ester by (2-iodoethyl)-carbamicacid tert-butyl ester.

Step B—Preparation of7-(2-tert-Butoxycarbonylamino-ethoxy)-4-oxo-4H-quinolizine-2-carboxylicAcid.

This compound was synthesized from7-(2-tert-butoxycarbonylamino-ethoxy)-4-oxo-4H-quinolizine-2-carboxylicacid methyl ester using the procedure described in step G of thepreparation of compound XIII.

Step C—Preparation of(S)-2-Benzenesulfonylamino-3-{[7-(2-tert-butoxycarbonylamino-ethoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionicAcid tert-butyl Ester.

This compound was prepared from7-(2-tert-butoxycarbonylamino-ethoxy)-4-oxo-4H-quinolizine-2-carboxylicacid using the procedure described in step A of the preparation ofcompound XIV.

Step D—Preparation of(S)-3-{[7-(2-Amino-ethoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-2-benzenesulfonylamino-propionicAcid Trifluoroacetic Acid Salt (Compound XIX).

This compound was prepared from(S)-2-benzenesulfonylamino-3-{[7-(2-tert-butoxycarbonylamino-ethoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionicacid tert-butyl ester (94% yield) of pure desired product as a yellowsolid using the procedure described in step B of the preparation ofcompound XIV. The compound was characterized with by ¹HNMR (400 MHz,CD₃OD) δ: 3.50-3.57 (m, 3H), 3.78-3.83 (dd, J=13.5 and 5.0 Hz, 1H),4.26-4.30 (dd, J=8.5 and 5.0 Hz, 1H), 4.40-4.42 (m, 1H), 6.85 (s, 1H),7.24 (s, 1H), 7.45-7.48 (m, 4H), 7.79 (d, J=9.5 Hz, 1H), 7.85-7.87 (m,2H), 8.63 (s, 1H).

Compound XX:(S)-2-Benzenesulfonylamino-3-{[7-(2-guanidino-ethoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionicAcid Hydrochloride

Step A—Preparation of compound XX from compound XIX.

Following the procedure described for the preparation of compound XVfrom compound XIV, compound XIX (20 mg, 0.034 mmol) afforded 9 mg (47%yield) of pure compound XX as a yellow solid which was characterized by¹HNMR (400 MHz, CD₃OD) δ: 3.50-3.56 (dd, J=13.5 and 9.0 Hz, 1H),3.74-3.76 (m, 2H), 3.79-3.84 (dd, J=13.5 and 5.0 Hz, 1H), 4.26-4.29 (dd,J=8.5 and 5.0 Hz, 1H), 4.35-4.38 (m, 2H), 7.08 (s, 1H), 7.43-7.48 (m,3H), 7.56 (s, 1H), 7.68 (d, J=9.5 Hz, 1H), 7.84-7.86 (dd, J=8.0 and 2.5Hz, 1H), 8.03 (d, J=9.5 Hz, 1H), 8.75 (s, 1H).

Compound XXI: 3-{[7-(3-Amino-propoxy)-4-oxo-4H-quinolizine-2carbonyl]-amino}-2-(pyrimidin-2-ylamino)-propionic Acid Hydrochloride

Step A—Preparation of3-{[7-(3-tert-Butoxycarbonylamino-propoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-2-(pyrimidin-2-ylamino)-propionicAcid Methyl Ester.

This compound was synthesized from7-(3-tert-butoxycarbonylamino-propoxy)-4-oxo-4H-quinolizine-2-carboxylicacid using the procedure described in the preparation of compound XIV(step A) replacing 3-amino-2-benzenesulfonylamino-propionic acidtert-butyl ester hydrochloride by2-methoxycarbonyl-2-(pyrimidin-2-ylamino)-ethyl-ammonium chloride.

Step B—Preparation of3-{[7-(3-tert-butoxycarbonylamino-propoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-2-(pyrimidin-2-ylamino)-propionicAcid.

To a solution of3-{[7-(3-tert-butoxycarbonylamino-propoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-2-(pyrimidin-2-ylamino)-propionicacid methyl ester (42 mg, 0.078 mmol) in THF (1 ml) and water (1 ml) wasadded lithium hydroxide monchydrate (3.9 mg, 0.093 mmol). The mixturewas stirred at room temperature for 0.5 hr. and THF was removed. Theresidue was diluted with CH₂Cl₂, acidified with 5% KHSO₄ solution andextracted with CH₂Cl₂ (3×75 ml). The extracts were combined, washed withwater (10 ml), brine (10 ml), dried and evaporated yielding 35 mg ofacid.

Step C—Preparation of3-([7-(3-Amino-propoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino)-2-(pyrimidin-2-ylamino)-propionicAcid Hydrochloride (Compound XXI).

A mixture of3-{[7-(3-tert-butoxycarbonylamino-propoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-2-(pyrimidin-2-ylamino)-propionicacid (35 mg)in 4N HCl in dioxane (6 ml) was stirred for 0.5 hr at roomtemperature. The reaction mixture was evaporated down to dryness. NMRshowed presence of small amount of starting material. The aboveprocedure was repeated with 4N HCl in dioxane (room temperature, 45minutes). The mixture was evaporated to dryness, triturated with ether,dissolved in water (6 ml) and lyophilized yielding pure product (XXI)(30 mg, 77%). Which was characterized by ¹H NMR (400 MHz, CD₃CD) δ:8.42-8.92 (3H, broad signal with one doublet (J=2.2 Hz) in the middle),7.90 (1H, d, J=9.6 Hz), 7.53 (!H, dd, J=2.3, 9.5 Hz), 7.34 (1H, d, J=1.3Hz), 7.08 (1H, t, J=5.3 Hz), 6.89 (1H, d, J=1.7 Hz), 5.06 (1H, dd,J=4.2, 6.5 Hz), 4.30 (2H, t, J=5.8 Hz), 4.14 (1H, dd, J=4.2, 14.1 Hz),3.93 (1H, dd, J=6.6, 14.1 Hz), 3.21(2H, t, J=7.2 Hz), 2.22-2.29 (2H, m).

Compound XXII:3-{[7-(3-Guanidino-propoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-2-(pyrimidin-2-ylamino)-propionicAcid Hydrochloride

Step A—Preparation of Compound XXII from Compound XXI.

Following the procedure described for the preparation of compound XVfrom compound XIV, compound XXI (19 mg, 0.038 mmol) afforded 13 mg (63%yield) of pure compound XXII which was characterized by ¹HNMR (400 MHz,CD₃OD) δ: 8.47-8.86 (3H, broad signal with a doublet (J=1.9 Hz) in themiddle), 7.91 (1H, d, J=9.6 Hz), 7.54 (1H along with a part of amidesignal, dd, J=2.2, 9.5 Hz), 7.36 (1H, singlet), 7.10 (1H, t, J=5.3 Hz),6.90 (1H, d, J=1.5 Hz), 5.07 (1H, dd, J=4.1, 6.4 Hz), 4.26 (2H, t, J=5.9Hz), 4.15 (1H, dd, J=4.2, 14.1 Hz), 3.94 (1H, dd, J=6.6, 14.1 Hz),3.44-3.49 (2H, m), 2.14-2.21 (2H, m).

Compound XXIII:(S)-3-{[7-(3-Amino-propoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-2-(benzenesulfonyl-methyl-amino)-propionicAcid Trifluoroacetic Acid Salt

Step A—Preparation of(S)-2-Benzenesulfonyl-methyl-amino-3-{[7-(3-tert-butoxycarbonylamino-propoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionicAcid tert-butyl Ester.

(S)-2-benzenesulfonylamino-3-{[7-(3-tert-butoxycarbonylamino-propoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionicacid tert-butyl ester(38 mg, 0.065 mmol) was treated with methyl iodide(0.4 ml) in acetone (2.5 ml) in presence of anhydrous potassiumcarbonate (50 mg) for 16 hrs at room temperature. The reaction mixturewas diluted with dichloromethane, washed with water, 0.1 N HCl, dilutesodium bicarbonate, water, brine, dried and evaporated. The puremethylated product was obtained by passing the crude through a column ofsilica gel (CH₂Cl₂-acetone mixtures as eluents (yield: 32 mg, 82%).

Step B—Preparation of(S)-3-{[7-(3-Amino-propoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-2-(benzenesulfonyl-methyl-amino)-propionicAcid Trifluoroacetic Acid Salt (Compound XXIII).

(S)-2-benzenesulfonyl-methyl-amino-3-{[7-(3-tert-butoxycarbonylamino-propoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionicacid tert-butyl ester (32 mg, 0.053 mmol) was treated withtrifluoroacetic acid (1 ml) in dichloromethane (1 ml) for 3.5 hrs atroom temperature. The reaction mixture was evaporated to dryness,triturated with ether (2×10 ml), dissolved in water and lyophilizedyielding (XXIII) (26 mg, 79%)which was characterized by ¹H NMR (400 MHz,CD₃OD) δ: 8.71 (¹H, broad singlet), 7.83-7.89 (3H, m), 7.46-7.50 (4H,m), 7.33 (1H, broad singlet), 6.94 (1H, broad singlet), 5.00-5.02 (1H,m), 4.31 (2H, broad signal), 3.85-3.88 (1H, m), 3.73-3.79 (1H, m), 3.22(2H, t, J=6.5 Hz), 2.91 (3H, s), 2.25-2.26 (2H, m).

Compound XXIV:(S)-2-(Benzenesulfonyl-methyl-amino)-3-{[7-(3-guanidino-propoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionicAcid Hydrochloride

Step A—Preparation of compound XXIV from compound XXIII.

Following the procedure described for the preparation of compound XVfrom compound XIV, compound XXIII (22 mg, 0.036 mmol) afforded 12 mg(57% yield) of pure compound XXIV which was characterized by ¹HNMR (400MHz, CD₃OD) δ: 8.85 (part of amide proton), 8.72 (1H, d, J=2 Hz), 7.89(1H, d, J=9.6 Hz), 7.83 (2H, dd, J=1.2, 7.7 Hz), 7.43-7.53 (4H, m), 7.35(1H, s), 6.94 (1H, d, J=1.6 Hz), 5.05 (1H, dd, J=4.5, 10.6 Hz), 4.27(2H, t, J=5.9 Hz), 3.88 (1H, dd, J=4.5, 14.1 Hz) 3.75 (1H, dd, J=10.7,13.9 Hz), 3.44-3.49 (2H, m), 2.91 (3H, s), 2.15-2.21 (2H, m).

Compound XXV:(S)-2-Benzenesulfonylamino-3-({4-oxo-7-[3-(pyrimidin-2-ylamino)-propoxy]-4H-quinolizine-2-carbonyl}-amino)-propionicAcid

Step A—Preparation of7-(3-Amino-propoxy)-4-oxo-4H-quinolizine-2-carboxylic Acid Methyl EsterTrifluoroacetic Acid Salt.

To a mixture of7-(3-tert-butoxycarbonylamino-propoxy)-4-oxo-4H-quinolizine-2-carboxylicacid methyl ester (480 mg, 1.275 mmol) in dichloromethane (12 ml) wasadded trifluoroacetic acid (12 ml). The mixture was stirred for 1 hourat room temperature and concentrated. Trituration of the crude in ethergave a bright yellow solid which was used as such for the next step.

Step B—Preparation of4-oxo-7-[3-(Pyrimidin-2-ylamino)-propoxy]-4H-quinolizine-2-carboxylicAcid Methyl Ester.

A mixture of 7-(3-amino-propoxy)-4-oxo-4H-quinolizine-2-carboxylic acidmethyl ester trifluoroacetic acid salt (50 mg, 0.181 mmol), 2-bromopyrimidine (29 mg, 181 mmol) and diisopropylethylamine (32 μl, 0.181mmol) in anhydrous DMF (0.2 ml) and anhydrous THF (1.6 ml) was stirredovernight at 70° C., concentrated and flash chromatographed (0-5%methanol in dichloromethane) to give 33.6 mg (52% yield) of desiredproduct as a yellow solid.

Step C—Preparation of4-oxo-7-[3-(Pyrimidin-2-ylamino)-propoxyl-4H-quinolizine-2-carboxylicAcid.

This compound was synthesized from4-oxo-7-[3-(pyrimidin-2-ylamino)-propoxy]-4H-quinolizine-2-carboxylicacid methyl ester in 91% yield using the procedure described in step Gof the preparation of compound XIII.

Step D—Preparation of(S)-2-Benzenesulfonylamino-3-({4-oxo-7-[3-(pyrimidin-2-ylamino)-propoxy]-4H-quinolizine-2-carbonyl)-amino)-propionicAcid tert-butyl Ester.

To a mixture of4-oxo-7-[3-(pyrimidin-2-ylamino)-propoxy]-4H-quinolizine-2-carboxylicacid (6.9 mg, 0.020 mmol), was added HATU (9.9 mg, 0.026 mmol),(S)-3-amino-2-benzenesulfonylamino-propionic acid tert-butyl esterhydrochloride (8.1 mg, 0.024 mmol) and collidine (19 μl, 0.140 mmol).The mixture was stirred for 45 minutes, concentrated and flashchromatographed (0-5% methanol in dichiloromethane) to give 10.3 mg (82%yield) of desired product.

Step E—Preparation of(S)-2-Benzenesulfonylamino-3-({4-oxo-7-[3-(pyrimidin-2-ylamino)-propoxy]-4H-quinolizine-2-carbonyl}-amino)-propionicAcid (Compound XXV).

To a mixture of(S)-2-Benzenesulfonylamino-3-(14-oxo-7-[3-(pyrimidin-2-ylamino)-propoxy]-4H-quinolizine-2-carbonyl}-amino)-propionicacid tert-butyl ester (10.0 mg, 0.016 mmol) in anhydrous dichloromethane(0.5 ml) was added trifluoroacetic acid (0.5 ml). The mixture wasstirred for 5 hours at room temperature, concentrated and flashchromatographed (ethanol:dichloromethane; 7:3) to give 3.7 mg (56%yield) of desired product which was characterized by ¹HNMR (400 MHz,CD₃OD) δ: 2.16-2.22 (m, 2H), 3.54-3.60 (dd, J=13.5 and 8.5 Hz, 1H),3.61-3.64 (m 2H), 3.73-3.78 (dd, J=13.5 and 4.5 Hz, 1H), 3.80-3.83 (m,1H), 4.25-4.28 (m, 2H), 6.57-6.59 (m, 1H), 6.94 (d, J=1.5 Hz, 1H), 7.34(s, 1H), 7.47-7.65 (m, 4H), 7.81-7.93 (m, 3H), 8.25 (d, J=5.0 Hz, 2H),8.68 (d, J=2.0 Hz, 1H).

Compound XXVI:3-[(7-Aminomethyl-4-oxo-4H-quinolizine-2-carbonyl)-amino]-2-benzenesulfonylamino-propionicAcid Trifluoroacetic Acid Salt

Step A—Preparation of 7-Cyano-4-oxo-4H-quinolizine-2-carboxylic AcidMethyl Ester.

To a mixture of 6-methyl-nicotinonitrile (1.000 g, 8.465 mmol) inanhydrous dioxane (80 ml) was added SeO₂ (9.392g, 84.645 mmol). Themixture was stirred at reflux for 7 hours, concentrated in vacuo and thecrude was flash chromatographed (0-25% ethyl acetate in dichloromethane)to give 825 mg of pure desired aldehyde. To a mixture of2-(diethoxy-phosphoryl)-succinic acid dimethyl ester (2.647g, 9.377mmol) in anhydrous THF (52 ml) was added NaH 60% in oil (0.375 g, 9.377mmol). The mixture was stirred for 30 minutes, cooled to 0° C. and asolution of the aldehyde in anhydrous THF (10 ml) was added slowly (themixture becomes dark red). The mixture was stirred for 1.5 hour at roomtemperature, quenched with water and extracted with dichloromethane(3×). The combined organic layers were washed with water and dried(MgSO₄). Removal of the solvent gave the crude desired product which waswashed and triturated in ether. Filtration in vacuo gave 891 mg of puredesired product (46% overall yield).

Step B—Preparation of 7-Aminomethyl-4-oxo-4H-quinolizine-2-carboxylicAcid Methyl Ester Hydrochloride.

To a solution of 7-cyano-4-oxo-4H-quinolizine-2-carboxylic acid methylester (50 mg, 0.218 mmol) in methanol was added Pd/C (10%) (40 mg). Tothis solution was added HCl in dioxane (4N, 3 ml) and the reactionmixture was stirred under hydrogen atmosphere at room temperature for 20min. The mixture was then filtered and evaporated. The crude product wastriturated with ether to give pure amine salt as a yellow solid in highyield (80%).

Step C—Preparation of7-(tert-Butoxycarbonylamino-methyl)-4-oxo-4H-quinolizine-2-carboxylicAcid Methyl Ester.

To a solution of 7-aminomethyl-4-oxo-4H-quinolizine-2-carboxylic acidmethyl ester hydrochloride (70 mg, 0.26 mmol) in dimethylformamide (3mL) was added triethylamine (0.04 mL, 0.286 mmol) and BOC anhydride (74mg, 0.339 mmol). The mixture was stirred for three hours then thesolution was evaporated to dryness. The mixture was diluted in ethylacetate washed with an aqueous solution of citric acid 5% and extractedwith ethyl acetate (3×). The combined organic phases were dried andsolvents were evaporated to give the desired product.

Step D—Preparation of7-(tert-Butoxycarbonylauino-methyl)-4-oxo-4H-quinolizine-2-carboxylicAcid.

To a solution of7-(tert-Butoxycarbonylamino-methyl)-4-oxo-4H-quinolizine-2-carboxylicacid methyl ester (30 mg, 0.09 mmol) in acetonitrile (1 mL) was addedlithium hydroxide (32 mg, 1.35 mmol) in water (1 mL). The mixture wasstirred for 3 hours then acidified to pH 4 with acetic acid. The mixturewas extracted using ethyl acetate (3×40 mL) dred over magnesium sulfate,evaporated to dryness to give the desired compound which was used assuch.

Step E—Preparation of(S)-2-Benzenesulfonylamino-3-{[7-(tert-Butoxycarbonylamino-methyl)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionicAcid tert-Butyl Ester.

To a solution of7-(tert-Butoxycarbonylamino-methyl)-4-oxo-4H-quinolizine-2-carboxylicacid (29 mg, 0.09 mmol) in dimethylformamide (0.3 mL) was added(S)-3-amino-2-benzenesulfonylamino-propionic acid tert-butyl esterhydrochloride (37 mg, 0.11 mmol), HATU (45 mg, 0.12 mmol) and collidine(0.084 mL, 0.63 mmol). The mixture was stirred for one hour then thedimethylformamide was evaporated. The residue was diluted with ethylacetate, washed with 10% aqueous HCl, water then brine. Drying withmagnesium sulfate followed by filtration and evaporation gave a cruderesidue which was purified by flash chromatography 100% ethyl acetate togive the desired product (21.2 mg).

Step F—Preparation of3-[(7-Aminomethyl-4-oxo-4H-quinolizine-2-carbonyl)-amino]-2-benzenesulfonylamino-propionicAcid Trifluoroacetic Acid Salt (Compound XXVI).

To a solution of(S)-2-Benzenesulfonylamino-3-{[7-(tert-butoxycarbonylamino-methyl)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionicacid tert-butyl ester (21.2 mg, 0.035 mmol) in dichloromethane (2 mL)was added trifluoroacetic acid (2 mL). The mixture was stirredovernight, evaporated to dryness and triturated in ether (3×) anddichloromethane (1×). The solid was dried and characterized to yield 62%(10 mg, 0.022 mmol) of the title compound which was characterized by¹HNMR (400 MHz, CD₃OD) δ: 9.03 (s, 1H), 7.93-7.83 (m, 3H), 7.64 (dd, 1H,J=9, 1.5 Hz), 7.55-7.45 (m, 3H), 7.26 (s, 1H), 6.92 (d, 1H, J=1.5 Hz),4.29 (s, 2H), 4.22 (dd, 1H, J=7.5, 5 Hz), 3.81-3.77 (dd, 1H, J=13.5, 5Hz), 3.55-3.45 (m, 1H).

Compound XXVII:(S)-2-Benzenesulfonylamino-3-[(7-guanidinomethyl-4-oxo-4H-quinolizine-2-carbonyl)-amino]-propionicAcid Hydrochloride Route 1

Step A—Preparation of7-bis-BOC-Guanidinomethyl-4-oxo-4H-quinolizine-2-carboxylic Acid MethylEster.

7-aminomethyl-4-oxo-4H-quinolizine-2-carboxylic acted methyl esterhydrochloride (50 mg, 0.18 mmol) was treated withtert-butoxycarbonylimino-pyrazol-1-yl-methyl)-carbamic acid tert-butylester (see Compound VIII—step C) (65 mg, 0.20 mmol) anddiisopropylethylamine (0.04 ml) in DMF (10 ml). The mixture was stirredat room temperature overnight. Solvent was evaporated and the residuewas chromatographed on silica gel using EtOAc: Hexanes (6:4) as eluentgiving the title compound in 820% yield as a yellow solid.

Step B—Preparation of7-bis-BOC-Guanidinomethyl-4-oxo-4H-quinolizine-2-carboxylic Acid.

To a solution of7-bis-BOC-guanidinomethyl-4-oxo-4H-quinolizine-2-carboxylic acid methylester (51 mg, 0.11 mmol) in CH₃CN/H₂O (1:1) was added LiOH (26 mg, 1.1mmol) and the reaction mixture was stirred at room temperature for 3hrs. The solvents were evaporated and the residue was neutralized withacetic acid and extracted with EtOAc. The combined organic layers weredried and solvent was evaporated under vacuum. The crude product waspurified on silica gel column chromatography using 10% MeOH/ETOAc togive pure desired material as a yellow solid in high yield.

Step C—Preparation of(S)-2-Benzenesulfonylamino-3-((7-bis-BOC-Guanidinomethyl-4-oxo-4H-quinolizine-2-carbonyl)-amino]-propionicAcid tert-butyl Ester.

The 7-bis-BOC-guanidinomethyl-4-oxo-4H-quinolizine-2-carboxyiic acidfrom step B was treated with(S)-3-amino-2-benzenesulfonylamino-propionic acid tert-butyl esterhydrochloride (48 mg, 0.144 mmol), HOBT (20 mg, 0.146 mmol) and EDC (28mg, 0.146 mmol) in DMF (20 ml). The mixture was then stirred at roomtemperature overnight. The solvent was evaporated and dried and thecrude product was purified on silica gel column chromatography usingETOAc/Hex (8:2)affording the pure desired product as yellow solid (70mg, 85% yield).

Step D—Preparation of(S)-2-Benzenesulfonylamino-3-[(7-guanidinomethyl-4-oxo-4H-quinolizine-2-carbonyl)-amino]-propionicAcid Hydrochloride (Compound XXVII).

Deprotection using the conditions described in the preparation ofcompound XXVI (step F) gave after purification on silica gelchromatography using EtOH: NH₄OH: H₂O (8:1:1) as eluent the expectedproduct as a yellow solid which was characterized by ¹HNMR (300 MHz,CD₃OD) δ: 7.91 (m, 2H), 7.5 (m, 3H), 6.78 (s, 1H), 6.54 (s, 1H), 4.49(m, 1H), 4.22 (m, 1H), 3.2-3.9 (m, 4H), 3.07 (m, 3H), 2.43 (m, 1H), 2.15(m, 1H), 1.66 (m, 1H).

Route 2

Step E—Preparation of(S)-2-Benzenesulfonylamino-3-[(7-guanidinomethyl-4-oxo-4H-quinolizine-2-carbonyl)-amino]-propionicAcid Hydrochloride (Compound XXVII).

Compound XXVII could also be prepared from compound XXVI using theprocedure described in the preparation of compound XV from compound XIV.

Compound XXVIII: (2S, 7R) and (2S,7S)-3-[(7-Aminomethyl-4-oxo-6,7,8,9-tetrahydro-4H-quinolizine-2-carbonyl)-amino]-2-benzenesulfonylamino-propionicAcid Trifluoroacetic Acid Salt

Step A—Preparation of(+/−)-7-(tert-Butoxycarbonylamino-methyl)-4-oxo-6,7,8,9-tetrahydro-4H-quinolizine-2-carboxylicAcid Methyl Ester.

This compound was synthesized using the procedures described in step Band C for the preparation of compound XXVI starting with the samematerial except that the hydrogenation step was extended in time toallow additional reduction of the quinolizinone ring.

Step B—Preparation of(+/−)-7-(tert-Butoxycarbonylamino-methyl)-4-oxo-6,7,8,9-tetrahydro-4H-quinolizine-2-carboxylicAcid.

To a solution of(+/−)-7-(tert-butoxycarbonylamino-methyl)-4-oxo-6,7,8,9-tetrahydro-4H-quinolizine-2-carboxylicacid methyl ester (45 mg, 0.14 mmol) in CH₃CN/H₂O (1:1) was added LiOH(33 mg, 1.35 mmol) and the reaction mixture was stirred at roomtemperature for 3 hrs. The mixture was evaporated and neutralized withacetic acid and extracted with ETOAc. The solvent was evaporated undervacuum and dried. The crude product was purified on silica gel columnchromatography using 10% (MeOH /ETOAc)affording pure desired material in88% yield.

Step C—Preparation of (2S, 7R) and (2S,7S)-2-Benzenesulfonylamino-3-{[7-(tert-butoxycarbonylamino-methyl)-4-oxo-6,7,8,9-tetrahydro-4H-quinolizine-2-carbonyl]-amino}-propionicAcid tert-butyl Ester.

(+/−)-7-(tert-butoxycarbonylamino-methyl)-4-oxo-6,7,8,9-tetrahydro-4H-quinolizine-2-carboxylicacid from the previous step was treated with(S)-3-amino-2-benzenesulfonylamino-propionic acid tert-butyl esterhydrochloride (45 mg, 0.14 mmol), HATU (80 mg, 0.21 mmol) and collidine(1.13 mmol, 0.15 ml) in DMF(20 ml). The mixture was stirred at roomtemperature overnight. The solvent was evaporated and dried and thecrude product was purified on silica gel column chromatography usingETOAc/Hex (8:2) affording the title as a yellow solid.

Step D—Preparation of (2S, 7R) and (2S,7S)-3-[(7-Aminomethyl-4-oxo-6,7,8,9-tetrahydro-4H-quinolizine-2-carbonyl)-amino]-2-benzenesulfonylamino-propionicAcid Trifluoroacetic Acid Salt (Compound XXVIII).

To a solution of (2S, 7R) and (2S,7S)-2-benzenesulfonylamino-3-{[7-(tert-butoxycarbonylamino-methyl)-4-oxo-6,7,8,9-tetrahydro-4H-quinolizine-2-carbonyl]-amino}-propionicacid tert-butyl ester (50 mg, 0.082 mmol) in dichloromethane was addeddiisopropylamine (0.11, 0.02 ml). TMSI (0.03 mL) was then added at roomtemperature and the reaction mixture was stirred at this temperature for3 hrs. The mixture was neutralized with 5% HCl (5 ml), 5% NaHCO₃ (10 ml)and the extract was dried and evaporated. The crude product was purifiedon silica gel column chromatography using ethanol:NH₄OH: water (8:2:1).This gave pure desired compound as a colorless solid which wascharacterized by ¹HNMR (300 Mhz, CD₃OD) δ: 7.91 (m, 2H), 7.55(m, 3H),6.78 (s, 1H), 6.53 (s, 1H), 4.5 (m, 1H), 4.22 (m, 1H), 3.2-3.8 (m, 4H),3.05 (m, 3H), 2.4 (m, 1H), 2.15 (m, 1H), 1.66 (m, 1H)

Compound XXIX: (2S, 7R) and (2S,7S)-2-Benzenesulfonylamino-3-[(7-guanidinomethyl-4-oxo-6,7,8,9-tetrahydro-4H-quinolizine-2-carbonyl)-amino]-propionicAcid

Step A—Preparation of Compound XXIX From Compound XXVIII.

Following the procedure described for the preparation of compound XVfrom compound XIV, compound XXVIII afforded compound XXIX as a colorlesssolid which was characterized by ¹HNMR (400 MHz, CD₃OD) δ: 7.94 (m, 2H),7.65 (m, 3H), 6.80 (s, 1H), 6.63 (s, 1H), 4.4 (m, 1H), 4.18 (m, 1H),3.1-3.8 (m, 4H), 3.05 (m, 3H) 2.4 (m, 1H), 2.18 (m, 1H), 1.67 (m, 1H)for the mixture of diastereomers.

Compound XXX:(S)-3-{[8-(3-Amino-propoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-2-benzenesulfonylamino-propionicAcid Trifluoroacetic Acid Salt

Step A—Preparation of 4-Benzyloxy-2-methyl-pyridine.

A mixture of sodium hydride (60% in oil, 640 mg, 16 mmol) and DMSO (6ml) was stirred at room temperature for 5 minutes. The suspension washeld at 100° C. for 15 minutes. It was cooled to room temperature andbenzyl alcohol (1.65 ml, 15.9 mmol) was added. The mixture was stirredat 80° C. for 10 minutes. It was cooled to room temperature and4-chloro-2-methyl-pyridine (1.7 g, 13.3 mmol) was added slowly. Themixture was stirred at room temperature for 40 minutes and at 80° C. for20 minutes. It was cooled and saturated ammonium chloride solution (10ml) was added. The mixture was extracted with ethyl acetate (250 ml) andthe extract was washed with water (3×10 ml), brine (10 ml) dried andevaporated. The solid residue was triturated with hexane-ether mixture(2:1) to obtain pure crystalline product (2 g, 75%)

Step B—Preparation of 8-hydroxy-4-oxo-4H-quinolizine-2-carboxylic acidmethyl ester.

The title compound was obtained from 4-benzyloxy-2-methyl-pyridine viathe same sequence as that described in the preparation of compound XIII(steps B, C, D and E)

Step C—Preparation of8-(3-tert-Butoxycarbonylamino-propoxy)-4-oxo-4H-quinolizine-2-carboxylicAcid.

The title compound was prepared from8-hydroxy-4-oxo-4H-quinolizine-2-carboxylic acid methyl ester using theprocedures described in the preparation of compound XIII (steps F and G)

Step D—Preparation of(S)-2-Benzenesulfonylamino-3-{[8-(3-tert-butoxycarbonylamino-propoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionicAcid tert-butyl Ester.

The title compound was obtained from8-(3-tert-butoxycarbonylamino-propoxy)-4-oxo-4H-quinolizine-2-carboxylicacid using the procedure described in step A of the preparation ofcompound XIV.

Step E—Preparation of(S)-3-{[8-(3-Amino-propoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-2-benzenesulfonylamino-propionicAcid Trifluoroacetic Acid Salt (Compound XXX).

(S)-2-Benzenesulfonylamino-3-{[8-(3-tert-butoxycarbonylamino-propoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionicacid tert-butyl ester (38 mg, 0.059 mmol) was dissolved indichloromethane (1 ml) and trifluoroacetic acid (1 ml) was added. Themixture was stirred for 3.5 hrs at room temperature. It was evaporatedto dryness, triturated with ether (2×10 ml) dissolved in water andlyophilized to obtain the product as yellow solid (34 mg, 95%) which wascharacterized by ¹HNMR (400 MHz, CD₃OD) δ: 9.03 (1H, d, J=7.8 Hz), 7.87(2H, d, J=7.2 Hz), 7.50 (3H, d, J=7.5 Hz), 7.21 (1H, s), 7.07 (1H, s),7.04 (1H, d, J=7.9 Hz), 6.61 (1H, s), 4.32-4.34 (2H, m), 4.20-4.22 (1H,m), 3.81 (1H, dd, J=4.6, 13.4 Hz), 3.52 (1H, dd, J=8.7, 13.2 Hz), 3.22(2H, t, J=6.8 Hz), 2.24-2.27 (2H, m).

Compound XXXI:(S)-2-Benzenesulfonylamino-3-{[8-(3-guanidino-propoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino)-propionicAcid Hydrochloride

Step A—Preparation of Compound XXXI From Compound XXX.

To a solution of(S)-3-{[8-(3-Amino-propoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-2-benzenesulfonylamino-propionicAcid Trifluoroacetic Acid Salt (Compound XXX) (15 mg, 0.025 mmol) in DMF(0.5 ml) and water (0.5 ml) was added 1H-pyrazole-1-carboxamidinehydrochloride (PCA) (6 mg, 0.041 mmol) and diisopropylethylamine (13 μl,0.075 mmol). The mixture was stirred at room temperature for 3.5 hrs andat 60° C. for 4.5 hrs It was evaporated to dryness and passed through acolumn of silica gel eluted with EtOH-H₂O-NH₄OH (8:1:1). Free base thusobtained was triturated with ether (2×10 ml), dissolved in a 1:1 mixtureof water and 0.1 N HCl and lyophilized yielding a yellow solid (7.9 mg,56%) which was characterized by ¹HNMR (400 MHz, CD₃OD) δ: 9.06 (1H, d,J=7.7 Hz), 7.85 (2H, dd, J=1.6, 7.4 Hz), 7.45-7.53 (3H, m), 7.30 (1H, d,J=2.5 Hz), 7.16 (1H, broad s), 7.11 (1H, dd, J=2.2, 7.7 Hz), 6.66 (1H,broad s), 4.31 (2H, t, J=S.S Hz), 4.26 (1H, dd, J=4.9, 8.8 Hz), 3.79(1H, dd, J=4.9, 13.5 Hz), 3.43-3.53 (3H, m), 2.14-2.19 (2H, m).

Compound XXXII:(S)-3-{[8-(4-Amino-butoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-2-benzenesulfonylamino-propionicAcid Trifluoroacetic Acid Salt

Step A—Preparation of8-(4-tert-butoxycarbonylamino-butoxy)-4-oxo-4H-quinolizine-2-carboxylicAcid.

The title compound was obtained via the procedure described for thepreparation of compound XXX (step C) replacing (3-iodopropyl)-carbamicacid tert-butyl ester by (4-iodobutyl)-carbamic Acid tert-Butyl Ester inthe Alkylation Step.

Step B—Preparation of(S)-2-benzenesulfonylamino-3-{[8-(4-tert-butoxycarbonylamino-butoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionicAcid tert-butyl Ester.

The title compound was obtained via the procedure described for thepreparation of compound XXX (step D).

Step C—Preparation of(S)-3-([8-(4-Amino-butoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-2-benzenesulfonylamino-propionicAcid trifluoroacetic Acid Salt (Compound XXXII).

Using the procedure described for the preparation of compound XXX (stepE),(S)-2-benzenesulfonylamino-3-{[8-(4-tert-butoxycarbonylamino-butoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionicacid tert-butyl ester (38 mg, 0.058 mmol) was treated withtrifluoroacetic acid in dichloromethane to afford compound XXXII (32 mg,90%) as a yellow solid which was characterized by ¹HNMR (400 MHz, CD₃OD)δ: 9.06 (1H, d, J=8.0 Hz), 7.86 (2H, dd, J=1.2, 7.7 Hz), 7.46-7.54 (3H,m), 7.23 (1H, d, J=2.5 Hz), 7.07 (1H, d, J=1.2 Hz), 7.03 (1H, dd, J=2.7,8.0 Hz), 6.59 (1H, d, J=1.6 Hz), 4.27 (2H, t, J=5.7 Hz), 4.22 (1H, dd,J=5.1, 8.6 Hz), 3.79 (1H, dd, J=5.0, 13.4 Hz), 3.51 (1H, dd, J=8.6, 13.5Hz), 3.06 (2H, t, J=7.4 Hz), 1.88-2.01 (4H, 2 multiplets).

Compound XXXIII:(S)-2-Benzenesulfonylamino-3-{[8-(4-guanidino-butoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionicAcid Hydrochloride

Step A—Preparation of Compound XXXIII From Compound XXXII.

(S)-3-{[8-(4-Amino-butoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-2-benzenesulfonylamino-propionicacid trifluoroacetic acid salt (compound XXXII) (25 mg, 0.041 mmol) wastreated with 1H-pyrazole-1-carboxamidine hydrochloride (9.5 mg, 0.065mmol) and diisopropylethylamine (2241, 0.126 mmol) in DMF (0.6 ml) andwater (0.6 ml) at 60° C. for 6.5 hrs. The purification procedure wasthat described for compound XXXI and gave pure compound XXXIII (12 mg,51%) which was characterized by ¹HNMR (400 MHz, CD₃OD) δ: 9.08 (1H, d,J=8.0 Hz), 7.86 (2H, dd, J=1.6, 8.0 Hz), 7.45-7.51 (3H, m), 7.27 (1H, d,J=2.4 Hz), 7.11 (1H, s), 7.07 (1H, dd, J=2.7, 8.0 Hz), 6.61 (1H, d,J=1.5 Hz), 4.23-4.29 (3H, m), 3.78 (1H, dd, J=5.1, 13.6 Hz), 3.51 (1H,dd, J=8.7, 13.4 Hz), 1.93-1.99, 1.80-1.87 (2H each, multiplet).

Compound XXXIV:(S)-3-{[8-(S-Amino-pentyloxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-2-benzenesulfonylamino-propionicAcid Trifluoroacetic Acid Salt

Step A—Preparation of8-(5-tert-butoxycarbonylamino-pentyloxy)-4-oxo-4H-quinolizine-2-carboxylicAcid.

The title compound was obtained via the procedure described for thepreparation of compound XXX (step C) replacing (3-iodopropyl)-carbamicacid tert-butyl ester by (5-iodopentyl)-carbamic acid tert-butyl esterin the alkylation step.

Step B—Preparation of(S)-2-Benzenesulfonylamino-3-{[8-(5-tert-butoxycarbonylamino-pentyloxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionicAcid tert-butyl Ester.

The title compound was obtained via the procedure described for thepreparation of compound XXX (step D).

Step C—Preparation of(S)-3-{[8-(5-Amino-pentyloxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-2-benzenesulfonylamino-propionicAcid Trifluoroacetic Acid Salt (Compound XXXIV).

Using the procedure described for the preparation of compound XXX (stepE),(S)-2-benzenesulfonylamino-3-{[8-(5-tert-butoxycarbonylamino-pentyloxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionicacid tert-butyl ester (42 mg, 0.063 mmol) was treated withtrifluoroacetic acid in dichloromethane to afford compound XXXIV (34 mg,86%) as a yellow solid which was characterized by ¹HNMR (400 MHz, CD₃OD)δ: 9.04 (1H, d, J=7.9 Hz), 7.86 (2H, dd, J=1.2, 7.7 Hz), 7.46-7.54 (3H,m), 7.21 (1H, d, J=2.5 Hz), 7.06 (1H, d, J=1.1 Hz), 7.02 (1H, dd, J=2.7,8.0 Hz), 6.58 (1H, d, J=1.6 Hz), 4.21-4.25 (3H, m), 3.79 (1H,dd, J=5.0,13.5 Hz), 3.52 (1H, dd, J=8.5, 13.4 Hz), 2.99 (2H, t, J=7.4 Hz),1.92-1.99, 1.74-1.82, 1.61-1.68 (6H, 3 multiplets).

Compound XXXV:(S)2-Benzenesulfonylamino-3-{[8-(5-guanidino-pentyloxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}propionicAcid Hydrochloride

Step A—Preparation of Compound XXXV From Compound XXXIV.

(S)-3-{[8-(5-Amino-pentyloxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-2-benzenesulfonylamino-propionicacid trifluoroacetic acid salt (compound XXXIV) (27 mg, 0.043 mmol) wastreated with 1H-pyrazole-1-carboxamidine hydrochloride (10 mg, 0.068mmol) and diisopropylethylamine (23 μl, 0.132 mmol) in DMF (0.7 ml) andwater (0.7 ml) at 60° C. for 6.5 hrs. The purification procedure wasthat described for compound XXXI and gave pure compound XXXV (13 mg,51%) which was characterized by ¹HNMR (400 MHz, CD₃OD) δ: 9.08 (1H, d,J=7.9 Hz), 7.86 (2H, d, J=6.3 Hz), 7.40-7.49 (3H, m), 7.25 (1H, s),7.05-7.08 (2H, m), 6.59 (1H, s) 4.25 (3H, t, J=4.7 Hz), 3.77 (1H, dd,J=4.8, 13.5 Hz), 3.48-3.54 (1H, m), 3.24 (2H, t, J=6.7 Hz), 1.62-1.94(6H, 3 multiplets).

Compound XXXVI:(+/−)-3-{[8-(2-Amino-ethylamino)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-3-phenyl-propionicAcid

Step A—Preparation of 8-chloro-4-oxo-4H-quinolizine-3-carboxylic AcidEthyl Ester.

This compound was synthesized using the methodology described an thepreparation of compound I (step A) from 4-chloro-2-methyl-pyridinereplacing n-butyllithium by lithium diisopropylamide in the additionreaction.

Step B—Preparation of 8-Chloro-4-oxo-4H-quinolizine-3-carboxylic Acid.

To a stirring solution of 8-Chloro-4-oxo-4H-quinolizine-3-carboxylicacid ethyl ester (500 mg, 1.99 mmol) in THF (20 ml) at room temperaturewas added aqueous LiOH solution (204 mg, 4.86 mmol, LiOH .H₂O in 12 mlH₂O). The mixture was stirred at room temperature for 4 h then acidifiedwith conc. HCl to pH 5. The organic solvent was evaporated and thedesired acid was collected by filtration (400 mg, 90%).

Step C—Preparation of(+/−)-3-[(8-chloro-4-oxo-4H-quinolizine-3-carbonyl)-amino]-3-phenyl-propionicAcid ethyl Ester.

To a stirring mixture of 8-Chloro-4-oxo-4H-quinolizine-3-carboxylic acid(22 mg, 0.098 mmol) in anhydrous DMF (1.5 ml) at room temperature wassequentially added (+/−)-3-amino-3-phenyl-propionic acid ethyl esterhydrochloride (28.4 mg, 0.123 mmol), N-methylmorpholine (32.4 μl, 0.295mmol) and O-(7-azabenzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (48.6 mg, 0.128 mmol). The resulting mixture wasallowed to stir at room temperature for 2 h. The solvent was removedunder vacuum and the resulting residue was subjected to a silica gelchromatography (Rex:EtOAc=1:1 to pure EtOAc) to give desired product asyellowish solid (32 mg, 81%).

Step D—Preparation of(+/−)-3-{[8-(2-tert-Butoxycarbonylamino-ethylamino)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-3-phenyl-propionicAcid Ethyl Ester.

To solution of(+/−)-3-[(8-Chloro-4-oxo-4H-quinolizine-3-carbonyl)-amino]-3-phenyl-propionicacid ethyl ester (32 mg, 0.080 mmol) in anhydrous pyridine (0.7 ml) atroom temperature were sequentially added N-Boc-1,3-diaminopropane (30.9mg, 0.19 mmol)and triethylamine (31.4 μl, 0.23 mmol). The resultingmixture was heated at 60° C. for 18 h. The solvent was removed undervacuum and the resulting residue subjected to a silica gelchromatography (EtOAc to EtOAc: MeOH=9:1) to give the desired product asyellowish solid (30 mg, 73%)

Step E—Preparation of(+/−)-3-{[8-(2-tert-Butoxycarbonylamino-ethylamino)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-3-phenyl-propionicAcid.

To a stirring solution of(+/−)-3-{[8-(2-tert-butoxycarbonylamino-ethylamino)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-3-phenyl-propionicacid ethyl ester (30 mg, 0.058 mmol), in THF (1.5 ml) at roomtemperature was added aqueous lithium hydroxide monohydrate solution(5.6 mg, 0.133 mmol, in 1 ml H₂O). The mixture was stirred at roomtemperature for 4 h. The organic solvent was evaporated and the mixturethen neutralized with HCl (1M solution in ether). The desired acid wascollected by filtration and used for next step without furtherpurification (26 mg, 92%).

Step F—Preparation of(+/−)-3-{[8-(2-Amino-ethylamino)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-3-phenyl-propionicAcid (Compound XXXVI).

To a stirred solution of(+/−)-3-{[8-(2-tert-butoxycarbonylamino-ethylamino)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-3-phenyl-propionicacid (20.5 mg, 0.042 mmol) in dichloromethane (1 ml) at room temperaturewas added trifluoroacetic acid (1 ml). The resulting mixture was stirredat room temperature for 45 min. The solvent was removed under vacuum andthe resulting residue was subjected to a silica gel chromatography(EtOH:H₂O: NH₄OH, 90:5:5) to give desired product which was furtherlyophilized to afford a yellowish solid (30 mg, 73%) which wascharacterized by ¹HNMR (400 MHz, D₂O) δ: 2.58-2.65 (m, 2H), 2.90-3.10(m, 2H), 3.15-3.25 (m, 2H), 5.21 (m, 1H), 6.0-8.7 (m, 10H).

Compound XXXVII:(+/−)-3-{[8-(2-Carbamimidoylsulfanyl-ethylamino)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-3-phenyl-propionicAcid Trifluoroacetic Acid Salt

Step A—Preparation of(+/−)3-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-phenyl-propionic Acid.

The title was prepared in 95% yield by the reaction of(+/−)-3-phenyl-3-aminopropionoic acid (10 g, 60.5 mmol) in aqeuous 10%K2CO3 (66.0 mmol) and 9-fluorenylmethyloxycarbonyl-N-hydroxysuccinimide(Fmoc-OSu, 16.875 g, 55 mmol) in dioxane (30 ml) according to theprocedure of G. F. Sigler (Biopolymers, 1983, 22, 2157-2162

Step B—Preparation of Resin Bound (+/−)-3-phenyl-3-aminopropionoate.

Wang resin (Novabiochem 0.79 mmol/g, 8.0 g, 5.6 mmol) was allowed toswell in dry DMF (50 ml).(+/−)3-(9H-fluoren-9-ylmethoxycarbonylamino)-3-phenyl-propionic acid(5.51 g, 14.2 mmol), HOBt (1.922 g, 14.2 mmol), PyBOP (7.3987 g, 14.2mmol) and diisopropylethylamine (5.6 ml, 35.6 mmol) were added and thesuspension was shaken for 16 h at rt. The resin was filtered and washedsuccessively with DMF(x5), MeOM (x5), dichloromethane (x5), MeOH (x5),dichloromethane (x5). The resulting resin was treated twice with a 25%solution of piperidine in DMF (50 ml) for 40 min each, then the resinwas filtered and washed as above and dried under reduced pressure givingthe desired compound (yield 8.9 g, gives a positive ninhydrin test).

Step C—Preparation of Resin Bound(+/−)-3-[(8-Chloro-4-oxo-4H-quinolizine-3-carbonyl)-amino]-3-phenyl-propionate.

Resin bound (+/−)-3-phenyl-3-aminopropionoate from step B (2.4 g, 1.9mmol) was allowed to swell in dry DMF (20 ml) then8-chloro-4-oxo-4H-quinolizine-3-carboxylic acid (0.695 g, 3.1 mmol),HOBt (0.271 g, 2.1 mmol), HATU (0.787 g, 2.1 mmol) and NMM (5 ml) wereadded in the mentioned order. The suspension was shaken at roomtemperature under nitrogen for 16 h. The resin was filtered and washedas above and dried under reduced pressure (yield 2.8 g, negativeninhydrin test).

Step D—Preparation of(+/−)-3-{[8-(2-Carbamimidoylsulfanyl-ethylamino)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-3-phenyl-propionicAcid Trifluoroacetic Acid Salt (Compound XXXVII).

Resin bound(+/−)-3-[(8-chloro-4-oxo-4H-quinolizine-3-carbonyl)-amino]-3-phenyl-propionatefrom step C (40 mg, 0.03 mmol) was allowed to swell in dry DMA (0.5 ml),then pyridine (0.5 ml), diisopropylethylamine (100 ml) and KI (10 mg,0.06 mmol) were added followed by 2-aminoethylisothiouronium bromidehydrobromide (13.3 mg, 0.047 mmol) and the suspension was placed in aore-heated Pierce Block at 66° C. and stirred gently for 16 h. The resinwas filtered and and washed as above and dried under reduced pressure.This resin was then treated with 95% TFA/H₂O (1 ml) for one hour and asecond time for two hours. The combined filtrates were concentrated andloaded on top of a flash silica gel column eluting with 10 MeOH/CH2Cl2.Fraction 12 to 14 were combined and concentrated leaving compound XXXVII(3.2 mg). LC/MS, M+1 for C₂₂H₂₃N₅O₄ (454)

Compound XXXVIII:(+/−)-3-({4-Oxo-8-[2-(pyridin-3-ylthiocarbamoylsulfanyl)-ethylamino]4H-quinolizine-3-carbonyl}-amino)-3-phenyl-propionicacid trifluoroacetic acid salt.

Step A—Preparation of Compound XXXVIII.

Resin bound(+/−)-3-[(8-chloro-4-oxo-4H-quinolizine-3-carbonyl)-amino]-3-phenyl-propionatefrom step C of the preparation of compound XXXVI (30 mg, 0.02 mmol) wasallowed to swell in dry DMA (0.5 ml), then pyridine (0.5 ml),diisopropylethylamine (100 ml) and KI (7 mg, 0.04 mmol) were addedfollowed by pyridin-3-yl-dithiocarbamic acid 2-amino-ethyl ester (7.5mg, 0.03 mmol) and the suspension was placed in a pre-heated PierceBlock at 66° C. and stirred gently for 16 h. The resin was filtered andwashed as above and dried under reduced pressure. This resin was treatedwith 95% TFA/H₂O (1 ml) for one hour and a second time for two hours.The combined filtrates were concentrated and loaded on top of a flashsilica column eluting with 10% MeOH/CH2Cl2. Fraction 6 to 8 werecombined and concentrated leaving compound XXXVIII(0.6 mg). LC/MS, M+1for C₂₇H₂₅N₅O₄S₂ (548).

Compound XXXIX:(+/−)-3-[(8-{Methyl-[2-(N-methyl-guanidino)-ethyl]-amino}-4-oxo-4H-quinolizine-3-carbonyl)-amino]-3-phenyl-propionicAcid Trifluoroacetic Acid Salt

Step A—Preparation of resin bound(+/−)-3-{[8-(2-methylamino-ethylamino)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-3-phenyl-propionate.

The title compound was prepared from resin bound(+/−)-3-[(8-chloro-4-oxo-4H-quinolizine-3-carbonyl)-amino]-3-phenyl-propionateas described in the preparation of compound XXXVII (step D).

Step B—Preparation of(+/−)-3-[(8-{Methyl-[2-(N-methyl-guanidino)-ethyl]-amino}-4-oxo-4H-quinolizine-3-carbonyl)-amino]-3-phenyl-propionicAcid Trifluoroacetic Acid Salt (Compound XXXIX).

Resin bound(+/−)-3-{[8-(2-methylamino-ethylamino)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-3-phenyl-propionate(50 mg, 0.04 mmol) was allowed to swell in DMF (0.3 ml), then ethyldiisopropyl amine (100 ml) and 1-H-pyrazole-1-carboxamidine HCl (20 mg,0.14 mmol) in H₂O (0.3 ml) were added and the suspension was shaken atrt for 16 h. The resin was filtered and washed with DMF, H₂O, MeOH,CH₂Cl₂, MeOH and CH₂Cl₂ and dried under reduced pressure. The resultingresin was treated with 95% TFA/H₂O (1 ml) for one hour and a second timefor two hours. The combined filtrates were concentrated (20 mg) andpurified with a Bond Elut C8 SPE cartridge eluting with 10-20%acetonitrile-water. Fraction 2 and 3 were combined and recrystalisedfrom MeOH/ether to give compound XXXIX, (1.6 mg). LC/MS M+1 forC₂₄H₂₈N₆O₄ (465).

Compound XL:(+/−)-3-{[8-(4-Carbamimidoyl-piperazin-1-yl)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-3-phenyl-propionicAcid Trifluoroacetic Acid Salt

Step A—Preparation of resin bound(+/−)-3-[(4-oxo-8-piperazin-1-yl-4H-quinolizine-3-carbonyl)-amino]-3-phenyl-propionate.

The title compound was prepared from resin bound(+/−)-3-[(8-chloro-4-oxo-4H-quinolizine-3-carbonyl)-amino]-3-phenyl-propionateas described in the preparation of compound XXXVII (step D).

Step B—Preparation of(+/−)-3-{[8-(4-Carbamimidoyl-piperazin-1-yl)-4-oxo-4H-quinolizine-3-carbonyl]-am1no}-3-phenyl-propionicAcid Trifluoroacetic Acid Salt (Compound XL).

Resin bound(+/−)-3-[(4-oxo-8-piperazin-1-yl-4H-quinolizine-3-carbonyl)-amino]-3-phenyl-propionate(50 mg, 0.04 mmol) was allowed to swell in DMF (0.3 ml), thendiisopropylethylamine (100 ml) and 1-H-pyrazole-1-carboxamidinehydrochloride (20 mg, 0.14 mmol) in H₂O (0.3 ml) were added and thesuspension was shaken at room temperature for 16 h. The resin wasfiltered and washed with DMF, H₂O, MeOH, dichloromethane, MeOH anddichloromethane and dried under reduced pressure. The resulting resinwas treated with 95% TFA/H₂O (1ml) for one hour and a second time fortwo hours. The combined filtrates were concentrated (20 mg) and purifiedwith a Bond Elut CB SPE cartridge eluting with 10-20%acetonitrile-water. Fraction one to six were combined and concentratedleaving compound XL, (12.5 mg). LC/MS M+1 for C₂₄H₂₆N₆O₄ (463). ¹H NMR(400 MHz, CD₃OD) 2.94 (m, 2H), 3.72 (bs, 8H), 5.58 (bs, 1H), 6.53 (d,1H), 6.77 (s, 1H), 7.05 (bs, 1H), 7.27-7.47 (m, 7H), 8.08 (d, 1H),9.03(d, 1H).

Compound XLI:(+/−)-3-{[8-(4-Guanidino-cyclohexylamino)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-3-phenyl-propionicAcid Trifluoroacetic Acid Salt

Step A—Preparation of Resin Bound(+/−)Trans-3{[8-(4-amino-cyclohexylamino)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-3-phenyl-propionate.

The title compound was prepared from resin bound(+/−)-3-[(8-chloro-4-oxo-4H-quinolizine-3-carbonyl)-amino]-3-phenyl-propionateas described in the preparation of compound XXXVII (step D).

Step B—Preparation of(+/−)-3-{[8-(4-Guanidino-cyclohexylamino)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-3-phenyl-propionicAcid Trifluoroacetic Acid Salt (Compound XLI).

Resin bound(+/−)trans-3{[8-(4-amino-cyclohexylamino)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-3-phenyl-propionate(50 mg, 0.04 mmol) was allowed to swell in DMF (0.3 ml), thendiisopropylethylamine (100 ml) and 1-H-pyrazole-1-carboxamidinehydrochloride (20 mg, 0.14 mmol) in H₂O (0.3 ml) were added and thesuspension was shaken at rt for 16 h. The resin was filtered and washedwith DMF, H₂O, MeOH, dichloromethane, MeOH and dichloromethane and driedunder reduced pressure. The resulting resin was treated with 95% TFA/H₂O(1 ml) for one hour and a second time for two hours. The combinedfiltrates were concentrated (20 mg) and purified with a Bond Elut C8 SPEcartridge eluting with 10-20% acetonitrile-water. Fraction 7 gavecompound XLI, (3 mg). LC/MS M+1 for C₂₆H₃₀N₆O₄ (491).

Compound XLII was prepared from7-bis-BOC-guanidinomethyl-4-oxo-4H-quinolizine-2-carboxylic acid and(+/−)-3-amino-3-(3,5-dichloro-phenyl)-propionic acid ethyl ester (CASregistry #147524-80-9) following a sequence similar to that describedfor the preparation of Compound XXVII.

Compound XLIII was prepared from7-bis-BOC-guanidinomethyl-4-oxo-4H-quinolizine-2-carboxylic acid and(+/−)-3-amino-3-pyridin-3-yl-propionic acid ethyl ester (CAS Registry#62247-22-7) following a sequence similar to that described for thepreparation of Compound XXVII.

Step A: Preparation of (+/−)-3-Amino-2-(pyrimidin-2-ylamino)-propionicAcid Methyl Ester

Methyl 2-amino-3-(N-t-butoxycarbonylamino)propionate (240 mg, 1.10 mmol)is obtained according to the disclosure found in Egbertson et al.,Synthetic Communications, vol. 23, pp. 703 et seq. (1993) incorporatedherein fully by reference. Methyl 2-amino-3-(N-t-butoxycarbonylamino)propionate was then mixed with 2-bromopyrimidine (350 mg, 2.20 mmol) andsodium carbonate (117 mg, 1.10 mmol) in DMF (1 mL). The resultingmixture was stirred at 100° C. for about 20 hours. The reaction mixturewas concentrated under vacuum and the residue was purified bychromatography eluting with 50% ethyl acetate in hexane and3-tert-butoxycarbonylamino-2-(pyrimidin-2-ylamino)-propionic acid methylester was obtained as a foam (174 mg, 53%).

A solution of3-tert-butoxycarbonylamino-2-(pyrimidin-2-ylamino)-propionic acid methylester (227 mg, 0.77 mmol) in HCl/dioxane (4 N, 5 mL) was stirred at roomtemperature for 1 hour. The solution was then concentrated to drynessand the residue was dissolved in water (20 mL). This solution was thenwashed with dichloromethane (2×10 mL) and hexanes (10 mL). The solutionwas then filtered and lyophilized to yield(+/−)-3-amino-2-(pyrimidin-2-ylamino)-propionic acid methyl ester as ayellow solid (185 mg, 90%).

Step B—Preparation of(+/−)-3-((7-Guanidinomethyl-4-oxo-4H-quinolizine-2-carbonyl)-amino)-2-(pyrimidin-2-ylamino)-propionicAcid bis-trifluoroacetic Acid Salt (Compound XLIV).

Compound XLIV was prepared from7-bis-BOC-guanidinomethyl-4-oxo-4H-quinolizine-2-carboxylic acid and(+/−)-3-amino-2-(pyrimidin-2-ylamino)-propionic acid methyl esterfollowing a sequence similar to chat described for the preparation ofCompound XXVII.

Compound XLV was prepared from(S)-2-Benzenesulfonylamino-3-[{7-(tert-butoxycarbonylamino-methyl)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionicacid tert-butyl ester via deprotection of the C-7 aminomethyl,introduction of the benzyloxycarbonyl group and hydrolysis of thet-butyl ester according to standard procedures.

Compound XLVI was prepared from(S)-2-Benzenesulfonylamino-3-{[7-(tert-butoxycarbonylamino-methyl)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionicacid tert-butyl ester via deprotection of the C-7 aminomethyl,alkylation with 2-bromo-pyrimidine and hydrolysis of the t-butyl esteraccording to standard procedures.

Compound XLVII was prepared from(S)-2-Benzenesulfonylamino-3-{[7-(tert-butoxycarbonylamino-methyl)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionicacid tert-butyl ester via deprotection of the C-7 aminomethyl,introduction of the benzylureido group and hydrolysis of the t-butylester according to standard procedures.

Compound XLVIII was prepared from7-bis-BOC-guanidinomethyl-4-oxo-4H-quinolizine-2-carboxylic acid and(S)-3-amino-2-benzyloxycarbonylamino-propionic acid methyl ester (CASRegistry #75760-11-1) following a sequence similar to that described forthe preparation of Compound XXVII.

Compound XLIX is prepared from7-bis-BOC-guan-dinomethyl-4-oxo-4H-quinolizine-2-carboxylic acid and(S)-3-amino-2-(2,4,6-trimethyl-benzenesulfonylamino)-propionic acidtert-butyl ester following a sequence similar to that described for thepreparation of Compound XXVII.

EXAMPLE 2 Fibrinogen Binding to Immobilized GP IIb-IIIa (α_(IIb)β₃) andα_(v)β₃

The wells of plastic microtiter plates were coated overnight at 4° C.with purified active GP IIb-IIIa (Calbiochem) or olacental αvβ3 at 0.5μg/ml (100 μL/well) in a buffer containing 150 mM NaCl, 20 mM Tris, pH7.4, and including 1 mM CaCl, for GP IIb-IIIa or 1 mM MgCl₂ and 0.2 mMMnCl₂ for (αvβ3. Blocking of nonspecific sites was achieved byincubating the wells with 35 mg/ml bovine serum albumin (BSA) for atleast 2 hours at 37° C. Biotinylated-fibrinogen (10 nM) was added to thewells in triplicate in the absence or presence of increasingconcentrations of compounds of interest (0.001-100 μM) and furtherincubated for 2 hours at 37° C.

Nonbound fibrinogen was removed by five washes with binding buffer.Avidin conjugated to alkaline phosphatase (Sigma), diluted in bindingbuffer, was added and incubated for two hours at 37° C. The plates werewashed five times with binding buffer, and after addition of thesubstrate PNPP (Pierce), the enzyme activity was measured by theabsorbance at 405 nm. The concentration of inhibitor required to inhibit50% of biotinylated-fibrinogen binding was defined as IC₅₀ determined bya nonlinear, sigmoidal dose response variable slope from the GraphPadPrism software.

The results of these tests are reported in Table 1 below.

TABLE 1 IC50 values for the fibrinogen binding assay COM- α_(v)β₃α_(IIb)β₃ POUND MOLECULAR STRUCTURE (μM) (μM) I

44 0.058 II

24 3.9 III

96 0.52 IV

8.7 0.033 V

>100 96 VI

>100 1.8 VII

92 0.0018 VIII

1.2 3.5 IX

1.3 0.0096 X

67 29 XI

20 20 XII

1.1 0.79 XIII

>100 5.3 XIV

17 0.00038 XV

0.015 0.0053 XVI

>100 1.5 XVII

5.1 0.00017 XVIII

2.2 0.0053 XIX

2.0 0.029 XX

0.10 0.0079 XXI

14 0.074 XXII

0.54 0.045 XXIII

>100 0.82 XXIV

58 1.3 XXV

15 1.25 XXVI

0.019 0.44 XXVII

0.015 0.25 XXVIII

0.37 0.10 XXIX

0.0042 0.094 XXX

17 0.11 XXXI

9.4 0.024 XXXII

12 0.0055 XXXIII

15 0.044 XXXIV

17 0.016 XXXV

15 1.5 XXXVI

19 10 XXXVII

8.2 0.17 XXXVIII

13 0.045 XXXIX

21 0.063 XL

1.9 0.000 00021 XLI

17 0.23 XLII

4.0 23 XLIII

0.72 14.8 XLIV

0.03 6 XLV

0.91 0.85 XLVI

0.29 3.5 XLVII

0.006 4.85 XVLIII

0.0049 2.6

EXAMPLE 3 Cell Attachment Assay

The wells of 96-well plates (Immunolon) were coated, by incubationovernight at 4° C., with 5 μg/ml of vitronectin or osteopontin, 10 μg/mlof fibronectin or 10 mg/ml BSA in PBS. The protein solution was flickedout and the wells were blocked with 10 mg/ml BSA (0.1 ml) for 1-2 hoursat 37° C. Cells [HT29 (ATOC), HMVEC (Cell Systems), K562 or K562transfected with αvβ3 (Blystone et al., 1994)] were loaded with afluorescent marker, 5-chloromethylfluorescein diacetate (MolecularProbes, Eugene, Or) for 1 hour at 37° C., then incubated in fresh mediumwithout the fluorescent marker for 1 hour.

Cells were lifted with trypsin-EDTA and washed two times with Hank'sbalanced salt solution (Sigma) supplemented with 1 mM MgCl₂. Cells(75,000 cells/well) were added to coated plates in triplicate andallowed to attach at 37° C. for 1 hour in the presence or absence ofspecific antibodies at 5 μ/ml or increasing concentrations of compoundsof interest (0.001-10 μM). Nonadherent cells were removed by gentlewashing twice with PBS. The adherent cells were solubilized with 1%triton X-100 and detected using a fluorescence plate reader (PerkinElmer).

The number of attached cells was calculated based upon starched curvesfor each cell line used in the experiment. Non-specific cell attachment(attachment to wells coated with BSA) was always less than 5%. Theresults presented are the average of triplicate samples andrepresentative of several separate assays.

The results of these tests are reported in Table 2 below.

TABLE 2 Cell Attachment Assay Results IC50 μM Integrin αvβ3 αvβ5 α5β1Cell Line K562 transfected αvβ3 HT29 K562 Compound Ligand Osteo-PontinVitro-nectin Vitro-Nectin Fibro-nectin XXIX 0.16 ± 0.01 ND 3.2 ± 1.6 >10XXVII 0.43 ± 0.18 ND 5.8 ± 3.6 >10 XV 0.5 ± 0.2 2.5 ± 1.5 10 ± 2  >10 XX2.3 ± 2.0 >10 >10 >10

EXAMPLE 4 Cell Proliferation and Cytotoxicity MTT Assay

The wells of microtiter plates were seeded with 2000 cells/well (T24),2500 cells/well (HT29), 5000 cells/well (HMVEC)or 2500 cells/well(IAFp2) in 100 μL, followed by an overnight culture for cell adhesion.The next day, the media is supplemented with 100 μL of increasingconcentrations of compounds of interest (0.001 to 10 μM). Followingculture for 72 hours,3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide (MTT;Sigma) at 2 mg/ml was added to each well (50 μL/well) and furtherincubated for 4 hours at 37° C. The medium was flicked out and 200 μL ofa 1:1 solution of ethanol:acetone followed by 25 μL of glycine buffer(0.1 M glycine, 0.1M NaCl, pH 10.5) is added and the color measured bythe absorbance at 570 nm.

The results of these tests are reported in Table 3 below.

TABLE 3 Cell Proliferation and Cytotoxicity Results IC50 μM IAFp2 HMVECHT29 T24 Skin Compound Endothelial Tumor Tumor Fibroblast XXIX 1.0 ± 0.2 13 >100 23 ± 0  XXVII 1.2 ± 0.4 >100 >100 >100 XV 16 ± 4  >100 >100  17XX 35 ± 22  100 >100  21

EXAMPLE 5 Chick Chorioallantoic Membrane (CAM) Assay

Shell-less Embryo Culture

Fertilized white leghorn chicken eggs (SPAFAS Inc., Norwich, Conn.) werereceived at day 0 and incubated for 3 days at 37 C with constanthumidity. On day 3, eggs were rinsed with 70% ethanol and opened into100 mm² tissue culture coated Petri dishes under aseptic conditions. Theembryos were then returned to a humidified 38 C incubator for 7-9additional days.

Mesh Assay

Vitrogen (Collagen Biomaterials, Palo Alto, Calif.) at a finalconcentration of 0.73 mg/ml and Matrigel (Becton Dickinson, Bedford,Mass.) at a final concentration of 10 mg/ml was directly pipetted ontoNylon meshes with 250 μm² openings which were cut into 4 mm×4 mm squaresand autoclaved. Polymerization of meshes were under aseptic conditions,on bacteriological Petri dishes. The polymerization conditions for eachsubstrate were identical; after mixing with or without 250 μg ofVPF/VEGF₁₆₅ (Peprotech, Rocky Hill, N.J.) and/or compounds of interest,40 μl were pipetted onto each mesh in a bacteriological Petri dish.

The Petri dish was placed in a humidified 37 C incubator with 5% CO₂ for30 minutes to allow polymerization followed by an incubation at 4 C for2 hours.

In a tissue culture enclosure, meshes were placed onto the periphery ofthe CAM of a day 12-14 embryo, excluding areas containing major vessels.The embryos were then returned to the humidified 38 C incubator with 3%CO₂ for 24 to 48 additional hours.

Visualization and Quantification of Vessels

Embryos were removed from the incubator and meshes were viewed under adissecting microscope for gross evaluation. Injection of 400 μl FITCdextran, MW 2,000,000 (Sigma, St. Louis, Mo.) through glassmicrocapillary tubes by infusion into the umbilical vein was performedat a rate of 200 μl per minute. The FITC dextran was allowed tocirculate for 5 minutes and 3.7% formaldehyde in PBS was applieddirectly on each mesh. The embryos were then incubated at 4 C for 5minutes and the meshes were dissected off the CAM and fixed in 3.7%formaldehyde for 10 minutes to overnight.

After fixation, meshes were mounted on slides with 90% glycerol in PBSand visualized on an inverted fluorescence microscope. A Nikon Diaphotwith a Sony DXC-151A camera attached to the side port was used forcapture of images and analysis was with the NIH Image 1.61 softwareprogram. For each mesh, 5 random staggered images (approximately 600 μmeach) were captured. The areas of high intensity were highlighted andmeasured. Results are expressed as ability to suppress capillaryformation after subtraction from negative control. Values werecalculated as i inhibition, considering 100% the capillary densityachieved by VPF in the presence of vitrogen alone minus the backgroundlevels in the absence of VPF. Negative values indicate angiogenicstimulation above the VPF positive control.

The results of these tests are reported in Table 4 below.

TABLE 4 CAM — Day 12 — 24 hr Treatment Concentration (μg/mesh) Compound3 (−VPF) 3 (+VPF) 17 (−VPF) 17 (+VPF) 33 (−VPF) 33 (+VPF) V 1%  7%  8% 9% 15% 20% XV 2%  7%  9%  7%  8% 10% XXVII 5%  9% 11% 12% 16% 19% XXIX4% 10%  8% 12% 13% 14% XL 4% −2% 10%  7%  9% 11%

Likewise, the specific pharmacological responses observed may varyaccording to and depending upon the particular active compound selectedor whether there are present pharmaceutical carriers, as well as thetype of formulation and mode of administration employed, and suchexpected variations or differences in the results are contemplated inaccordance with the objects and practices of the present invention. Itis intended, therefore, that the invention be limited only by the scopeof the claims which follow.

We claim:
 1. A compound of formula (I) or formula (II):

or a pharmaceutically acceptable salt or solvate thereof; wherein R1 andR4 are both H, R2 is —J—K—L, and R3 is —X—Y—Z; wherein J is selectedfrom the group consisting of: —(CH₂)_(m)—, —(CH₂)_(m)CR⁵≡CR⁷(CH₂)_(n)—,—(CH₂)_(m)CR⁵≡CR⁷(CH₂)_(n)—, —(CH₂)_(m)O(CH₂)_(n)—,—(CH₂)_(m)S(CH₂)_(n)—, —(CH₂)_(m)NR⁵(CH₂)_(n)—, —(CH₂)_(m)CO(CH₂)_(n)—,—(CH₂)_(m)CS(CH₂)_(n)—, —(CH₂)_(m)SO₂(CH₂)_(n)—, —(CH₂)_(m)SO(CH₂)_(n)—,—(CH₂)_(m)C(O)O(CH₂)_(n)—, —(CH₂)_(m)OC(O)(CH₂)_(n)—,—(CH₂)_(m)SO₂NR⁵(CH₂)_(n)—, —(CH₂)_(m)NR⁵SO₂(CH₂)_(n)—,—(CH₂)_(m)CONR⁵(CH₂)_(n)—, —(CH₂)_(m)NR⁵CO(CH₂)_(n)—,—(CH₂)_(m)NR⁵(CH₂)_(n)CONH—, —(CH₂)_(m)O(CH₂)_(n)CONH—,—(CH₂)_(m)NH(CH₂)_(n)SCSNR⁵—, —(CH₂)_(m)NH(CH₂)_(n)SCNHNH₂—, and anamine linked pyridine or pyrimidine, where m and n are independentlyintegers from 0-6; wherein K is selected from the group consisting of:—C₁₋₈alkyl—, —C₃₋₁₅cycloalkyl—, —C₆₋₁₅aryl—, —C₆₋₁₅aryl-C₁₋₈alkyl—,—C₁₋₈alkyl-C₆₋₁₅aryl—, —C₁₋₈alkenyl—, —C₁₋₈alkynyl—, —(CH₂)_(q)NR⁶—,—CONR⁶—, —NHC(O)OCH₂—C₆₋₈aryl—, —CNHNH₂—, a pyrimidine, a pyridine, andan amine linked pyridine or pyrimidine; wherein L is selected from thegroup consisting of a pyrimidine, —NHR¹², —NR¹³C(N)NHR¹², —C(N)NHR¹²,—C(O)NHR¹², —NR¹³C(O)NHR¹², —SC()NHR¹², —SC(S)NHR¹², —OC(N)NHR¹²,—OC(O)NHR¹², and —C(O)OR¹²; wherein X is selected from the groupconsisting of: —(CH₂)_(o)—, —(CH₂)_(o)CR⁵≡CR⁷(CH₂)_(p)—,—(CH₂)_(o)CR⁵≡CR⁷(CH₂)_(p)—, —(CH₂)_(o)O(CH₂)_(p)—,—(CH₂)_(o)S(CH₂)_(p)—, —(CH₂)_(o)NR⁵(CH₂)_(p)—, —(CH₂)_(m)CO(CH₂)_(n)—,—(CH₂)_(m)CS(CH₂)_(n)—, —(CH₂)_(o)SO₂(CH₂)_(p)—, —(CH₂)_(o)SO(CH₂)_(p)—,—(CH₂)_(o)C(O)O(CH₂)_(p)—, —(CH₂)_(o)OC(O)(CH₂)_(p)—,—(CH₂)_(o)SO₂NR⁵(CH₂)_(p)—, —(CH₂)_(o)NR⁵SO₂(CH₂)_(p)—,—(CH₂)_(o)CONR⁵(CH₂)_(p)—, —(CH₂)_(o)NR⁵CO(CH₂)_(p)—,—(CH₂)_(o)NR⁵CONR⁷(CH₂)_(p)—, —(CH₂)_(o)NR⁵(CH₂)_(p)CONH—,—(CH₂)_(o)O(CH₂)_(p)CONH—, —(CH₂)_(o)NH(CH₂)_(p)SCSNR⁵—, and—(CH₂)_(o)NH(CH₂)_(p)SCNHNH₂—, where o and p are independently integersfrom 0-6; wherein Y is selected from the group consisting of:—(CH₂)_(q)—, C₆ ₈aryl, a C₃₋₁₀cycloalkyl and

where q and r are independently integers of 0-4 and the sum of s and tis an integer of between 3 and 8; wherein Z is selected from the groupconsisting of —H, —COOH, —C(O)OR¹⁴ and —SO₂R¹⁴; wherein R⁵, R⁶, R⁷ andR¹³ are, for each structure they represent, independently selected fromthe group consisting of hydrogen, C₁₋₁₀alkyl, C₁₋₁₀alkenyl,C₁₋₁₀alkynyl, C₀₋₈alkylaryl, and C₃₋₁₀cycloalkyl; wherein R⁸, R⁹, R¹⁰,and R¹¹ are independently selected from the group consisting of H,alkyl, alkenyl, alkynyl, NHR⁵SO₂C₆₋₁₀aryl, C₆₋₁₀aryl,C₁₋₆alkyl-C₆₋₁₀aryl, a 5-10 member heterocycle, an amine linked 5-10membered heterocycle, and a 5-10 member heterocycle linked by aC₁₋₆alkyl, wherein said heterocycle is in each case selected from thegroup consisting of pyridine, pyrimidine, piperazine, pyrrole, furan,imidazole, oxazole, pyrazole, pyrroline, piperidine, morpholine,thiomorpholine, thiophene and pyrrolidine; wherein R¹² and R¹⁴ areindependently selected from the group consisting of —C₁₋₁₀alkyl,—C₃₋₁₀cycloalkyl, a —C₀₋₈alkyl-C₆₋₁₀aryl, and a 5-10 member heterocycleoptionally linked by a C₁₋₁₀alkyl or an amine, wherein said heterocycleis in each case selected from the group consisting of pyridine,pyrimidine, piperazine, pyrrole, furan, imidazole, oxazole, pyrazole,pyrroline, piperidine, morpholine, thiomorpholine, thiophene andpyrrolidine.
 2. A compound of claim 1, wherein said compound is offormula I.
 3. A compound of formula II:

or a pharmaceutically acceptable salt or solvate thereof; wherein one ofR1 and R2 is —J—K—L, and the other is H; wherein one of R3 and R4 is—X—Y—Z, and the other is H; wherein J is selected from the groupconsisting of: —(CH₂)_(m)—, —(CH₂)_(m)CR⁵≡CR⁷(CH₂)_(n)—,—(CH₂)_(m)CR⁵≡CR⁷(CH₂)_(n)—, —(CH₂)_(m)O(CH₂)_(n)—,—(CH₂)_(m)S(CH₂)_(n)—, —(CH₂)_(m)NR⁵(CH₂)_(n)—, —(CH₂)_(m)CO(CH₂)_(n)—,—(CH₂)_(m)CS(CH₂)_(n)—, —(CH₂)_(m)SO₂(CH₂)_(n)—, —(CH₂)_(m)SO(CH₂)_(n)—,—(CH₂)_(m)C(O)O(CH₂)_(n)—, —(CH₂)_(m)OC(O)(CH₂)_(n)—,—(CH₂)_(m)SO₂NR⁵(CH₂)_(n)—, —(CH₂)_(m)NR⁵SO₂(CH₂)_(n)—,—(CH₂)_(m)CONR⁵(CH₂)_(n)—, —(CH₂)_(m)NR⁵CO(CH₂)_(n)—,—(CH₂)_(m)NR⁵(CH₂)_(n)CONH—, —(CH₂)_(m)O(CH₂)_(n)CONH—,—(CH₂)_(m)NH(CH₂)_(n)SCSNR⁵—, —(CH₂)_(m)NH(CH₂)_(n)SCNHNH₂—, and anamine linked pyridine or pyrimidine, where m and n are independentlyintegers from 0-6; wherein K is selected from the group consisting of:—C₁₋₈alkyl—, —C₃₋₁₅cycloalkyl—, —C₆₋₁₅aryl—, —C₆₋₁₅aryl-C₁₋₈alkyl—,—C₁₋₈alkyl-C₆₋₁₅aryl—, —C₁₋₈alkenyl—, —C₁₋₈alkynyl—, —(CH₂)_(q)NR⁶—,—CONR⁶—, —NHC(O)OCH₂—C₆₋₈aryl—, —CNHNH₂—, a pyrimidine, a pyridine, andan amine linked pyridine or pyrimidine; wherein L is selected from thegroup consisting of —H, —C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl, a pyrimidine,—C₆₋₁₀aryl, —C₁₋₁₀alkyl-C₆₋₁₀aryl, —NHR¹², —NR¹³C(N)NHR¹², —C(N)NHR¹²,—C(O)NHR¹², —NR³C(O)NHR¹², —SC(N)NHR¹², —SC(S)NHR¹², —OC(N)NHR¹²,—OC(O)NHR¹², and —C(O)OR¹²; wherein X is selected from the groupconsisting of: —(CH₂)_(o)—, —(CH₂)_(o)CR⁵≡CR⁷(CH₂)_(p)—,—(CH₂)_(o)CR⁵≡CR⁷(CH₂)_(p)—, —(CH₂)_(o)(CH₂)_(p)—,—(CH₂)_(o)S(CH₂)_(p)—, —(CH₂)_(o)NR⁵(CH₂)_(p)—, —(CH₂)_(m)CO(CH₂)_(n)—,—(CH₂)_(m)CS(CH₂)_(n)—, —(CH₂)_(o)SO₂(CH₂)_(p)—, —(CH₂)_(o)SO(CH₂)_(p)—,—(CH₂)_(o)C(O)O(CH₂)_(p)—, —(CH₂)_(o)OC(O)(CH₂)_(p)—,—(CH₂)_(o)SO₂NR⁵(CH₂)_(p)—, —(CH₂)_(o)NR⁵SO₂(CH₂)_(p)—,—(CH₂)_(o)CONR⁵(CH₂)_(p)—, —(CH₂)_(o)NR⁵CO(CH₂)_(p)—,—(CH₂)_(o)NR⁵CONR⁷(CH₂)_(p)—, —(CH₂)_(o)NR⁵(CH₂)_(p)CONH—,—(CH₂)_(o)O(CH₂)_(p)CONH—, —(CH₂)_(o)NH(CH₂)_(p)SCSNR⁵—, and—(CH₂)_(o)NH(CH₂)_(p)SCNHNH₂—, where o and p are independently integersfrom 0-6; wherein Y is selected from the group consisting of—(CH₂)_(q)—, C₆₋₈aryl, a C₃₋₁₀cycloalkyl and

where q and r are independently integers of 0-4 and the sum of s and tis an integer of between 3 and 8; wherein Z is selected from the groupconsisting of —H, —COOH, —C(O)OR¹⁴ and —SO₂R¹⁴; wherein R⁵, R⁶, R⁷ andR¹³ are, for each structure they represent, independently selected fromthe group consisting of hydrogen, C₁₋₁₀alkyl, C₁₋₁₀alkenyl,C₁₋₁₀alkynyl, C₀₋₈alkylaryl, and C₃₋₁₀cycloalkyl; wherein R⁸, R⁹, R¹⁰,and R¹¹ are independently selected from the group consisting of H,alkyl, alkenyl, alkynyl, NHR⁵SO₂C₆₋₁₀aryl, C₆₋₁₀aryl,C₁₋₆alkyl-C₆₋₁₀aryl, a 5-10 member heterocycle, an amine linked 5-10membered heterocycle, and a 5-10 member heterocycle linked by aC₁₋₆alkyl, wherein said heterocycle is in each case selected from thegroup consisting of pyridine, pyrimidine, piperazine, pyrrole, furan,imidazole, oxazole, pyrazole, pyrroline, piperidine, morpholine,thiomorpholine, thiophene and pyrrolidine; wherein R¹² and R¹⁴ areindependently selected from the group consisting of —C₁₋₁₀alkyl,—C₃₋₁₀cycloalkyl, a —C₀₋₈alkyl-C₆₋₁₀aryl, and a 5-10 member heterocycleoptionally linked by a C₁₋₁₀alkyl or an amine, wherein said heterocycleis in each case selected from the group consisting of pyridine,pyrimidine, piperazine, pyrrole, furan, imidazole, oxazole, pyrazole,pyrroline, piperidine, morpholine, thiomorpholine, thiophene andpyrrolidine.
 4. A compound of formula (I) or formula (II):

or a pharmaceutically acceptable salt or solvate thereof; wherein R1 andR3 are both H, R2 is —J—K—L, and R4 is —X—Y—Z; wherein J is selectedfrom the group consisting of: —(CH₂)_(m)—, —(CH₂)_(m)CR⁵≡CR⁷(CH₂)_(n)—,—(CH₂)_(m)CR⁵≡CR⁷(CH₂)_(n)—, —(CH₂)_(m)O(CH₂)_(n)—,—(CH₂)_(m)S(CH₂)_(n)—, —(CH₂)_(m)NR⁵(CH₂)_(n)—, —(CH₂)_(m)CO(CH₂)_(n)—,—(CH₂)_(m)CS(CH₂)_(n)—, —(CH₂)_(m)SO₂(CH₂)_(n)—, —(CH₂)_(m)SO(CH₂)_(n)—,—(CH₂)_(m)C(O)O(CH₂)_(n)—, —(CH₂)_(m)OC(O)(CH₂)_(n)—,—(CH₂)_(m)SO₂NR⁵(CH₂)_(n)—, —(CH₂)_(m)NR⁵SO₂(CH₂)_(n)—,—(CH₂)_(m)CONR⁵(CH₂)_(n)—, —(CH₂)_(m)NR⁵CO(CH₂)_(n)—,—(CH₂)_(m)NR⁵(CH₂)_(n)CONH—, —(CH₂)_(m)O(CH₂)_(m)CONH—,—(CH₂)_(m)NH(CH₂)_(n)SCSNR⁵—, —(CH₂)_(m)NH(CH₂)_(n)SCNHNH₂—, and anamine linked pyridine or pyrimidine, where m and n are independentlyintegers from 0-6; wherein K is selected from the group consisting of:—C₁₋₈alkyl—, —C₃₋₁₅cycloalkyl—, —C₆₋₁₅aryl—, —C₆₋₁₅aryl-C₁₋₈alkyl—,—C₁₋₈alkyl-C₆₋₁₅aryl—, —C₁₋₈alkenyl—, —C₁₋₈alkynyl—, —(CH₂)_(q)NR⁶—,—CONR⁶—, —NHC(O)OCH₂—C₆₋₈aryl—, —CNHNH₂—, a pyrimidine, a pyridine, andan amine linked pyridine or pyrimidine; wherein L is selected from thegroup consisting of —H, —C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl, a pyrimidine,C₆₋₁₀aryl, —C₁₋₁₀alkyl-C₆₋₁₀aryl, —NHR¹², —NR¹³C(N)NHR¹², —C(N)NHR¹²,—C(O)NHR¹², —NR¹³C(O)NHR¹², —SC(N)NHR¹², —SC(S)NHR¹², —OC(N)NHR¹²,—OC(O)NHR¹², and —C(O)OR¹²; wherein X is selected from the groupconsisting of: —(CH₂)_(o)—, —(CH₂)_(o)CR⁵≡CR⁷(CH₂)_(p)—,—(CH₂)_(o)CR⁵≡CR⁷(CH₂)_(p)—, —(CH₂)_(o)O(CH₂)_(p)—,—(CH₂)_(o)S(CH₂)_(p)—, —(CH₂)_(o)NR⁵(CH₂)_(p)—, —(CH₂)_(m)CO(CH₂)_(n)—,—(CH₂)_(m)CS(CH₂)_(n)—, —(CH₂)_(o)SO₂(CH₂)_(p)—, —(CH₂)_(o)SO(CH₂)_(p)—,—(CH₂)_(o)C(O)O(CH₂)_(p)—, —(CH₂)_(o)OC(O)(CH₂)_(p)—,—(CH₂)_(o)SO₂NR⁵(CH₂)_(p)—, —(CH₂)_(o)NR⁵SO₂(CH₂)_(p)—,—(CH₂)_(o)CONR⁵(CH₂)_(p)—, —(CH₂)_(o)NR⁵CO(CH₂)_(p)—,—(CH₂)_(o)NR⁵CONR⁷(CH₂)_(p)—, —(CH₂)_(o)NR⁵(CH₂)_(p)CONH—,—(CH₂)_(o)O(CH₂)_(p)CONH—, —(CH₂)_(o)NH(CH₂)_(p)SCSNR⁵—, and—(CH₂)_(o)NH(CH₂)_(p)SCNHNH₂—, where o and p are independently integersfrom 0-6; wherein Y is selected from the group consisting of:—(CH₂)_(q)—, C₆₋₈aryl, a C₃₋₁₀cycloalkyl and

where q and r are independently integers of 0-4 and the sum of s and tis an integer of between 3 and 8; wherein Z is selected from the groupconsisting of —H, —COOH, —C(O)OR¹⁴ and —SO₂R¹⁴; wherein R⁵, R⁶, R⁷ andR¹³ are, for each structure they represent, independently selected fromthe group consisting of hydrogen, C₁₋₁₀alkyl, C₁₋₁₀alkenyl,C₁₋₁₀alkynyl, C₀₋₈alkylaryl, and C₃₋₁₀cycloalkyl wherein; wherein R⁸,R⁹, R¹⁰, and R¹¹ are independently selected from the group consisting ofH, alkyl, alkenyl, alkynyl, NHR⁵SO₂C₆₋₁₀aryl, C₆₋₁₀aryl,C₁₋₆alkyl-C₆₋₁₀aryl, a 5-10 member heterocycle, an amine linked 5-10membered heterocycle, and a 5-10 member heterocycle linked by aC₁₋₆alkyl, wherein said heterocycle is in each case selected from thegroup consisting of pyridine, pyrimidine, piperazine, pyrrole, furan,imidazole, oxazole, pyrazole, pyrroline, piperidine, morpholine,thiomorpholine, thiophene and pyrrolidine; wherein R¹² and R¹⁴ areindependently selected from the group consisting of —C₁₋₁₀alkyl,—C₃₋₁₀cycloalkyl, a —C₀₋₈alkyl-C₆₋₁₀aryl, and a 5-10 member heterocycleoptionally linked by a C₁₋₁₀alkyl or an amine, wherein said heterocycleis in each case selected from the group consisting of pyridine,pyrimidine, piperazine, pyrrole, furan, imidazole, oxazole, pyrazole,pyrroline, piperidine, morpholine, thiomorpholine, thiophene andpyrrolidine.
 5. A compound of formula (I) or formula (II):

or a pharmaceutically acceptable salt or solvate thereof; wherein R2 andR4 are both H, R1 is —J—K—L, and R3 is —X—Y—Z; wherein J is selectedfrom the group consisting of: —(CH₂)_(m)—, —(CH₂)_(m)CR^(≡CR)⁷(CH₂)_(n)—, —(CH₂)_(m)CR⁵≡CR⁷(CH₂)_(n)—, —(CH₂)_(m)O(CH₂)_(n)—,—(CH₂)_(m)S(CH₂)_(n)—, —(CH₂)_(m)NR⁵(CH₂)_(n)—, —(CH₂)_(m)CO(CH₂)_(n)—,—(CH₂)_(m)CS(CH₂)_(n)—, —(CH₂)_(m)SO₂(CH₂)_(n)—, —(CH₂)_(m)SO(CH₂)_(n)—,—(CH₂)_(m)C(O)O(CH₂)_(n)—, —(CH₂)_(m)OC(O)(CH₂)_(n)—,—(CH₂)_(m)SO₂NR⁵(CH2)_(n)—, —(CH₂)_(m)NR⁵SO₂(CH₂)_(n)—,—(CH₂)_(m)CONR⁵(CH₂)_(n)—, —(CH₂)_(m)NR⁵CO(CH₂)_(n)—,—(CH₂)_(m)NR⁵(CH₂)_(n)CONH—, —(CH₂)_(m)O(CH₂)_(n)CONH—,—(CH₂)_(m)NH(CH₂)_(n)SCSNR⁵—, —(CH₂)_(m)NH(CH₂)_(n)SCNHNH₂—, and anamine linked pyridine or pyrimidine, where m and n are independentlyintegers from 0-6; wherein K is selected from the group consisting of:—C₁₋₈alkyl—, —C₃₋₁₅cycloalkyl—, —C₆₋₁₅aryl—, —C₆₋₁₅aryl-C1-8alkyl—,—C₁₋₈alkyl-C₆₋₁₅aryl—, —C₁₋₈alkenyl—, —C₁₋₈alkynyl—, —(CH₂)_(q)NR⁶—,—CONR⁶—, —NHC(O)OCH₂—C₆₋₈aryl—, —CNHNH₂—, a pyrimidine, a pyridine, andan amine linked pyridine or pyrimidine; wherein L is selected from thegroup consisting of —H, —C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl, a pyrimidine,—C₆₋₁₀aryl, —C₁₋₁₀alkyl-C₆₋₁₀aryl, —NHR¹², —NR¹³C(N)NHR¹², —C(N)NHR¹²,—C(O)NHR¹², —NR¹³C(O)NHR¹², —SC(N)NHR¹², —SC(S)NHR¹², —OC(N)NHR¹²,—OC(O)NHR¹², and —C(O)OR¹²; wherein X is selected from the groupconsisting of: —(CH₂)_(o)—, —(CH₂)_(o)CR⁵≡CR⁷(CH₂)_(p)—,—(CH₂)_(o)CR⁵≡CR⁷(CH₂)_(p)—, —(CH₂)_(o)O(CH₂)_(p)—,—(CH₂)_(o)S(CH₂)_(p)—, —(CH₂)_(o)NR⁵(CH₂)_(p)—, —(CH₂)_(m)CO(CH₂)_(n)—,—(CH₂)_(m)CS(CH₂)_(n)—, —(CH₂)_(o)SO₂(CH₂)_(p)—, —(CH₂)_(o)SO(CH₂)_(p)—,—(CH₂)_(o)C(O)O(CH₂)_(p)—, —(CH₂)_(o)OC(O)(CH₂)_(p)—,—(CH₂)_(o)SO₂NR⁵(CH₂)_(p)—, —(CH₂)_(o)NR5SO₂(CH₂)_(p)—,—(CH₂)_(o)CONR⁵(CH₂)_(p)—, —(CH₂)_(o)NR⁵CO(CH₂)_(p)—,—(CH₂)_(o)NR⁵CONR⁷(CH₂)_(p)—, —(CH₂)_(o)NR⁵(CH₂)_(p)CONH—,—(CH₂)_(o)O(CH₂)_(p)CONH—, —(CH₂)_(o)NH(CH₂)_(p)SCSNR⁵—, and—(CH₂)_(o)NH(CH₂)_(p)SCNHNH₂—, where o and p are independently integersfrom 0-6; wherein Y is selected from the group consisting of:—(CH₂)_(q)—, C₆₋₈aryl, a C₃₋₁₀cycloalkyl and

where q and r are independently integers of 0-4 and the sum of s and tis an integer of between 3 and 8; wherein Z is selected from the groupconsisting of —H, —COOH, —C(O)OR¹⁴ and —SO₂R¹⁴; wherein R⁵, R⁶, R⁷ andR¹³ are, for each structure they represent, independently selected fromthe group consisting of hydrogen, C₁₋₁₀alkyl, C₁₋₁₀alkenyl,C₁₋₁₀alkynyl, C₀₋₈alkylaryl, and C₃₋₁₀cycloalkyl; wherein R⁸, R⁹, R¹⁰,and R¹¹ are independently selected from the group consisting of H,alkyl, alkenyl, alkynyl, NHR⁵SO₂C₆₋₁₀aryl, C₆₋₁₀aryl,C₁₋₆alkyl-C₆₋₁₀aryl, a 5-10 member heterocycle, an amine linked 5-10membered heterocycle, and a 5-10 member heterocycle linked by aC₁₋₆alkyl, wherein said heterocycle is in each case selected from thegroup consisting of pyridine, pyrimidine, piperazine, pyrrole, furan,imidazole, oxazole, pyrazole, pyrroline, piperidine, morpholine,thiomorpholine, thiophene and pyrrolidine; wherein R¹² and R¹⁴ areindependently selected from the group consisting of —C₁₋₁₀alkyl,—C₃₋₁₀cycloalkyl, a —C₀₋₈alkyl-C₆₋₁₀aryl, and a 5-10 member heterocycleoptionally linked by a C₁₋₁₀alkyl or an amine, wherein said heterocycleis in each case selected from the group consisting of pyridine,pyrimidine, piperazine, pyrrole, furan, imidazole, oxazole, pyrazole,pyrroline, piperidine, morpholine, thiomorpholine, thiophene andpyrrolidine.
 6. A compound of claim 1, wherein J is selected from thegroup consisting of: —(CH₂)_(m)—, —(CH₂)_(m)CR⁵≡CR⁷(CH₂)_(n)—,—(CH₂)_(m)CR⁵≡CR⁷(CH₂)_(n)—, —(CH₂)_(m)O(CH₂)_(n)—,—(CH₂)_(m)S(CH₂)_(n)—, —(CH₂)_(m)NR⁵(CH₂)_(n)—, —(CH₂)_(m)CO(CH₂)_(n)—,—(CH₂)_(m)CS(CH₂)_(n)—, —(CH₂)_(m)SO₂(CH₂)_(n)—, —(CH₂)_(m)SO(CH₂)_(n)—,—(CH₂)_(m)C(O)O(CH₂)_(n)—, —(CH₂)_(m)OC(O)(CH₂)_(n)—,—(CH₂)_(m)SO₂NR⁵(CH₂)_(n)—, —(CH₂)_(m)NR⁵SO₂(CH₂)_(n)—,—(CH₂)_(m)SO₂NR⁵(CH₂)_(n)—, —(CH₂)_(m)NR⁵SO₂(CH₂)_(n)—,—(CH₂)_(m)CONR⁵(CH₂)_(n)—, —(CH₂)_(m)NR⁵CO(CH₂)_(n)—, and an aminelinked pyrimidine, where m and n are independently integers from 0-6. 7.A compound of claim 1, wherein J is selected from the group consistingof —(CH₂)_(m)—, —(CH₂)_(m)CR⁵≡CR⁷(CH₂)_(n)—, —(CH₂)_(m)C≡C(CH₂)_(n)—,—(CH₂)_(m)O(CH₂)_(n)—, —(CH₂)_(m)S(CH₂)_(n)—, —(CH₂)_(m)NR⁵(CH₂)_(n)—,and an amine linked pyrimidine; and wherein m and n are independentlyintegers from 0-3.
 8. The compound of claim 7, wherein m is an integerbetween 0-1.
 9. The compound of claims 7, wherein m is
 0. 10. Thecompound of claim 7, wherein n is an integer between 0-1.
 11. Thecompound of claim 7, wherein n is
 0. 12. A compound of claim 7, whereinR⁵ and R⁷ are independently hydrogen or C₁alkyl, where C₁alkyl is CH₃.13. The compound of claim 7, wherein R⁶ and R⁷ are both hydrogen.
 14. Acompound of claim 1, wherein K is selected from the group consisting of:—C₁₋₈alkyl—, —C₃₋₁₅cycloalkyl—, —C₆₋₁₅aryl—, —C₆₋₁₅aryl-C₁₋₈alkyl—,—C₁₋₈alkyl-C₆₋₁₅aryl—, —C₁₋₈alkenyl—, —C₁₋₈alkynyl—, a pyridine, apyrimidine, and an amine linked pyridine or pyrimidine.
 15. A compoundof claim 1, wherein K is a —C₁₋₈alkyl— or a —C₃₋₁₅cycloalkyl—.
 16. Thecompound of claim 15, wherein K is a —C₁₋₃alkyl—.
 17. The compound ofclaim 15, wherein K is a —C₁alkyl—.
 18. The compound of claim 15,wherein K is a —C₅₋₈cycloalkyl—.
 19. The compound of claim 15, wherein Kis a —C₆cycloalkyl—.
 20. A compound of formula (I) or formula (II):

or a pharmaceutically acceptable salt or solvate thereof; wherein one ofR1 and R2 is —J—K—L, and the other is H; wherein one of R3 and R4 is—X—Y—Z, and the other is H; wherein J is selected from the groupconsisting of: —(CH₂)_(m)—, —(CH₂)_(m)CR⁵≡CR⁷(CH₂)_(n)—,—(CH₂)_(m)CR⁵≡CR⁷(CH₂)_(n)—, —(CH₂)_(m)O(CH₂)_(m)—,—(CH₂)_(m)S(CH₂)_(n)—, —(CH₂)_(m)NR⁵(CH₂)_(n)—, —(CH₂)_(m)CO(CH₂)_(n)—,—(CH₂)_(m)CS(CH₂)_(n)—, —(CH₂)_(m)SO₂(CH₂)_(n)—, —(CH₂)_(m)SO(CH₂)_(n)—,—(CH₂)_(m)C(O)O(CH₂)_(n)—, —(CH₂)_(m)OC(O)(CH₂)_(n)—,—(CH₂)_(m)SO₂NR⁵(CH₂)_(n)—, —(CH₂)_(m)NR⁵SO₂(CH₂)_(n)—,—(CH₂)_(m)CONR⁵(CH₂)_(n)—, —(CH₂)_(m)NR⁵CO(CH₂)_(n)—,—(CH₂)_(m)NR⁵(CH₂)_(n)CONH—, —(CH₂)_(m)O(CH₂)_(n)CONH—,—(CH₂)_(m)NH(CH₂)_(n)SCSNR⁵—, —(CH₂)_(m)NH(CH₂)_(n)SCNHNH₂—, and anamine linked pyridine or pyrimidine, where m and n are independentlyintegers from 0-6; wherein K is selected from the group consisting of:—C₁₋₈alkyl—, —C₃₋₁₅cycloalkyl—, —C₆₋₁₅aryl—, —C₆₋₁₅aryl-C₁₋₈alkyl—,—C₁₋₈alkyl-C₆₋₁₅aryl—, —C₁₋₈alkenyl—, —C₁₋₈alkynyl—, —(CH₂)_(q)NR⁶—,—CONR⁶—, —NHC(O)OCH₂—C₆₋₈aryl—, —CNHNH₂—, a pyrimidine, a pyridine, andan amine linked pyridine or pyrimidine; wherein L is selected from thegroup consisting of a pyrimidine, —NHR¹², —NR³C(N)NHR¹², —C(N)NHR¹²,—C(O)NHR¹², —NR¹³C(O)NHR¹², —SC(N)NHR¹², —SC(S)NHR¹², —OC(N)NHR¹²,—OC(O)NHR¹², and —C(O)OR¹²; wherein X is selected from the groupconsisting of: —(CH₂)_(o)—, —(CH₂)_(o)CR⁵≡CR⁷(CH₂)_(p)—,—(CH₂)_(o)CR⁵≡CR⁷(CH₂)_(p)—, —(CH₂)_(o)O(CH₂)_(p)—,—(CH₂)_(o)S(CH₂)_(p)—, —(CH₂)_(o)NR⁵(CH₂)_(p)—, —(CH₂)_(m)CO(CH₂)_(n)—,—(CH₂)_(m)CS(CH₂)_(n)—, —(CH₂)_(o)SO₂(CH₂)_(p)—, —(CH₂)_(o)SO(CH₂)_(p)—,—(CH₂)_(o)C(O)O(CH₂)_(p)—, —(CH₂)_(o)OC(O)(CH₂)_(p)—,—(CH₂)_(o)SO₂NR⁵(CH₂)_(p)—, —(CH₂)_(o)NR⁵SO₂(CH₂)_(p)—,—(CH₂)_(o)CONR⁵(CH₂)_(p)—, —(CH₂)_(o)NR⁵CO(CH₂)_(p)—,—(CH₂)_(o)NR⁵CONR⁷(CH₂)_(p)—, —(CH₂)_(o)NR⁵(CH₂)_(p)CONH—,—(CH₂)_(o)O(CH₂)_(p)CONH—, —(CH₂)_(o)NH(CH₂)_(p)SCSNR⁵—, and—(CH₂)_(o)NH(CH₂)_(p)SCNHNH₂—, where o and p are independently integersfrom 0-6; wherein Y is selected from the group consisting of:—(CH₂)_(q)—, C₆₋₈aryl, a C₃₋₁₀cycloalkyl and

where q and r are independently integers of 0-4 and the sum of s and tis an integer of between 3 and 8; wherein Z is selected from the groupconsisting of —H, —COOH, —C(O)OR¹⁴ and —SO₂R¹⁴; wherein R⁵, R⁶, R⁷ andR¹³ are, for each structure they represent, independently selected fromthe group consisting of hydrogen, C₁₋₁₀alkyl, C₁₋₁₀alkenyl,C₁₋₁₀alkynyl, C₀₋₈alkylaryl, and C₃₋₁₀cycloalkyl; wherein R⁸, R⁹, R¹⁰,and R¹¹ are independently selected from the group consisting of H,alkyl, alkenyl, alkynyl, NHR⁵SO₂C₆₋₁₀aryl, C₆₋₁₀aryl,C₆₋₁₀alkyl-C₆₋₁₀aryl, a 5-10 member heterocycle, an amine linked 5-10membered heterocycle, and a 5-10 member heterocycle linked by aC₁₋₆alkyl, wherein said heterocycle is in each case selected from thegroup consisting of pyridine, pyrimidine, piperazine, pyrrole, furan,imidazole, oxazole, pyrazole, pyrroline, piperidine, morpholine,thiomorpholine, thiophene and pyrrolidine; wherein R¹² and R¹⁴ areindependently selected from the group consisting of —C₁₋₁₀alkyl,—C₃₋₁₀cycloalkyl, a —C₀₋₈alkyl-C₆₋₁₀aryl, and a 5-10 member heterocycleoptionally linked by a C₁₋₁₀alkyl or an amine, wherein said heterocycleis in each case selected from the group consisting of pyridine,pyrimidine, piperazine, pyrrole, furan, imidazole, oxazole, pyrazole,pyrroline, piperidine, morpholine, thiomorpholine, thiophene andpyrrolidine.
 21. A compound of formula (I) or formula (II):

or a pharmaceutically acceptable salt or solvate thereof; wherein one ofR1 and R2 is —J—K—L, and the other is H; wherein one of R3 and R4 is—X—Y—Z, and the other is H; wherein J is selected from the groupconsisting of: —(CH₂)_(m)—, —(CH₂)_(m)CR⁵≡CR⁷(CH₂)_(n)—,—(CH₂)_(m)CR⁵≡CR⁷(CH₂)_(n)—, —(CH₂)_(m)O(CH₂)_(n)—,—(CH₂)_(m)S(CH₂)_(n)—, —(CH₂)_(m)NR⁵(CH₂)_(n)—, —(CH₂)_(m)CO(CH₂)_(n)—,—(CH₂)_(m)CS(CH₂)_(n)—, —(CH₂)_(m)SO₂(CH₂)_(n)—, —(CH₂)_(m)SO(CH₂)_(n)—,—(CH₂)_(m)C(O)O(CH₂)_(n)—, —(CH₂)_(m)OC(O)(CH₂)_(n)—,—(CH₂)_(m)SO₂NR⁵(CH₂)_(n)—, —(CH₂)_(m)NR⁵SO₂(CH₂)_(n)—,—(CH₂)_(m)CONR⁵(CH₂)_(n)—, —(CH₂)_(m)NR⁵CO(CH₂)_(n)—,—(CH₂)_(m)NR⁵(CH₂)_(n)CONH—, —(CH₂)_(m)O(CH₂)_(n)CONH—,—(CH₂)_(m)NH(CH₂)_(n)SCSNR⁵—, —(CH₂)_(m)NH(CH₂)_(n)SCNHNH₂—, and anamine linked pyridine or pyrimidine, where m and n are independentlyintegers from 0-6; wherein K is selected from the group consisting of:—C₁₋₈alkyl—, —C₃₋₁₅cycloalkyl—, —C₆₋₁₅aryl—, —C₆₋₁₅aryl-C₁₋₈alkyl—,—C₁₋₈alkyl-C₆₋₁₅aryl—, —C₁₋₈alkenyl—, —C₁₋₈alkynyl—, —(CH₂)_(q)NR⁶—,—CONR⁶—, —NHC(O)OCH₂—C₆₋₈aryl—, —CNHNH₂—, a pyrimidine, a pyridine, andan amine linked pyridine or pyrimidine; wherein L is selected from thegroup consisting of: a pyrimidine, C₆₋₁₀aryl, —NH₂R¹², —NR¹³C(N)NHR¹²,—C(N)NHR¹², —C(O)NHR¹², —NR³C(O)NHR¹², —SC(N)NHR₁₂, —SC(S)NHR¹², and—OC()NHR¹²; wherein X is selected from the group consisting of:—(CH₂)_(o)—, —(CH₂)_(o)CR⁵≡CR⁷(CH₂)_(p)—, —(CH₂)_(o)CR⁵≡CR⁷(CH₂)_(p)—,—(CH₂)_(o)O(CH₂)_(p)—, —(CH₂)_(o)S(CH₂)_(p)—, —(CH₂)_(o)NR⁵(CH₂)_(p)—,—(CH₂)_(m)CO(CH₂)_(n)—, —(CH₂)_(m)CS(CH₂)_(n)—, —(CH₂)_(o)SO₂(CH₂)_(p)—,—(CH₂)_(o)SO(CH₂)_(p)—, —(CH₂)_(o)C(O)O(CH₂)_(p)—,—(CH₂)_(o)OC(O)(CH₂)_(p)—, —(CH₂)_(o)SO₂NR⁵(CH₂)_(p)—,—(CH₂)_(o)NR⁵SO₂(CH₂)_(p)—, —(CH₂)_(o)CONR⁵(CH₂)_(p)—,—(CH₂)_(o)NR⁵CO(CH₂)_(p)—, —(CH₂)_(o)NR⁵CONR⁷(CH₂)_(p)—,—(CH₂)_(o)NR⁵(CH₂)_(p)CONH—, —(CH₂)_(o)O(CH₂)_(p)CONH—,—(CH₂)_(o)NH(CH₂)_(p)SCSNR⁵—, and —(CH₂)_(o)NH(CH₂)_(p)SCNHNH₂—, where oand p are independently integers from 0-6; wherein Y is selected fromthe group consisting of: —(CH₂)_(q)—, C₆₋₈aryl, a C₃₋₁₀cycloalkyl and

where q and r are independently integers of 0-4 and the sum of s and tis an integer of between 3 and 8; wherein Z is selected from the groupconsisting of —H, —COOH, —C(O)OR¹⁴ and —SO₂R¹⁴; wherein R⁵, R⁶, R⁷ andR¹³ are, for each structure they represent, independently selected fromthe group consisting of hydrogen, C₁₋₁₀alkyl, C₁₋₁₀alkenyl,C₁₋₁₀alkynyl, C₀₋₈alkylaryl, and C₃₋₁₀cycloalkyl; wherein R⁸, R⁹, R¹⁰,and R¹¹ are independently selected from the group consisting of H,alkyl, alkenyl, alkynyl, NHR⁵SO₂C₆₋₁₀aryl, C₆₋₁₀aryl,C₁₋₆alkyl-C₆₋₁₀aryl, a 5-10 member heterocycle, an amine linked 5-10membered heterocycle, and a 5-10 member heterocycle linked by aC₁₋₆alkyl, wherein said heterocycle is in each case selected from thegroup consisting of pyridine, pyrimidine, piperazine, pyrrole, furan,imidazole, oxazole, pyrazole, pyrroline, piperidine, morpholine,thiomorpholine, thiophene and pyrrolidine; wherein R¹² and R¹⁴ areindependently selected from the group consisting of —C₁₋₁₀alkyl,—C₃₋₁₀cycloalkyl, a —C₀₋₈alkyl-C₆₋₁₀aryl, and a 5-10 member heterocycleoptionally linked by a C₁₋₁₀alkyl or an amine, wherein said heterocycleis in each case selected from the group consisting of pyridine,pyrimidine, piperazine, pyrrole, furan, imidazole, oxazole, pyrazole,pyrroline, piperidine, morpholine, thiomorpholine, thiophene andpyrrolidine.
 22. A compound of claim 21, wherein R¹³ is a C₁₋₅alkyl. 23.A compound of claim 21, wherein R¹² is selected from the groupconsisting of —C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl, or a —C₀₋₈alkyl-C₆₋₁₀aryl,and a heterocycle optionally linked by a C₁₋₁₀alkyl, wherein saidheterocycle is selected from the group consisting of pyridine,pyrimidine, piperazine, pyrrole, furan, imidazole, oxazole, pyrazole,pyrroline, piperidine morpholine, thiomorpholine, thiophene andpyrrolidine.
 24. The compound of claim 21, wherein R¹² is a C₆aryloptionally linked by a C₁₋₂alkyl or an amine.
 25. A compound of claim21, wherein R¹² is a heterocycle optionally linked by a C₁₋₂alkyl or anamine, wherein said heterocycle is selected from the group consisting ofpyridine, pyrimidine, piperazine, pyrrole, furan, imidazole, oxazole,pyrazole, pyrroline, piperidine morpholine, thiomorpholine, thiopheneand pyrrolidine.
 26. A compound of formula (I) or formula (II):

or a pharmaceutically acceptable salt or solvate thereof; wherein one ofR1 and R2 is —J—K—L, and the other is H; wherein one of R3 and R4 is—X—Y—Z, and the other is H; wherein J is selected from the groupconsisting of: —(CH₂)_(m)—, —(CH₂)_(m)CR⁵≡CR⁷(CH₂)_(n)—,—(CH₂)_(m)CR⁵≡CR⁷(CH₂)_(n)—, —(CH₂)_(m)O(CH₂)_(n)—,—(CH₂)_(m)S(CH₂)_(n)—, —(CH₂)_(m)NR⁵(CH₂)_(n)—, —(CH₂)_(m)CO(CH₂)_(n)—,—(CH₂)_(m)CS(CH₂)_(n)—, —(CH₂)_(m)SO₂(CH₂)_(n)—, —(CH₂)_(m)SO(CH₂)_(n)—,—(CH₂)_(m)C(O)O(CH₂)_(n)—, —(CH₂)_(m)OC(O)(CH₂)_(n)—,—(CH₂)_(m)SO₂NR⁵(CH₂)_(n)—, —(CH₂)_(m)NR⁵SO₂(CH₂)_(n)—,—(CH₂)_(m)CONR⁵(CH₂)_(n)—, —(CH₂)_(m)NR⁵CO(CH₂)_(n)—,—(CH₂)_(m)NR⁵(CH₂)_(n)CONH—, —(CH₂)_(m)O(CH₂)_(n)CONH—,—(CH₂)_(m)NH(CH₂)_(n)SCSNR⁵—, —(CH₂)_(m)NH(CH₂)_(n)SCNHNH₂—, and anamine linked pyridine or pyrimidine, where m and n are independentlyintegers from 0-6; wherein K is selected from the group consisting of:—C₁₋₈alkyl—, —C₃₋₁₅cycloalkyl—, —C₆₋₁₅aryl—, —C₆₋₁₅aryl-C₁₋₈alkyl—,—C₁₋₈alkyl-C₆₋₁₅aryl—, —C₁₋₈alkenyl—, —C₁₋₈alkynyl—, —(CH₂)_(q)NR⁶—,—CONR⁶—, —NHC(O)OCH₂—C₆₋₈aryl—, —CNHNH₂—, a pyrimidine, a pyridine, andan amine linked pyridine or pyrimidine; wherein L is selected from thegroup consisting of —H, —C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl, a pyrimidine,—C₆₋₁₀aryl, —C₁₋₁₀alkyl-C₆₋₁₀aryl, —NHR¹², —NR³C(N)NHR¹², —C(N)NHR¹²,—C(O)NHR¹², —NR¹³C(O)NHR¹², —SC(N)NHR¹², —SC(S)NHR¹², —OC(N)NHR¹²,—OC(O)NHR¹², and —C(O)OR¹²; wherein X is selected from the groupconsisting of: —(CH₂)_(o)SO₂(CH₂)_(p)—, —(CH₂)_(o)C(O)O(CH₂)_(p)—,—(CH₂)_(o)OC(O)(CH₂)_(p)—, —(CH₂)_(o)SO₂NR⁵(CH₂)_(p)—,—(CH₂)_(o)NR⁵SO₂(CH₂)_(p)—, —(CH₂)_(o)CONR⁵(CH₂)_(p)—,—(CH₂)_(o)NR⁵CO(CH₂)_(p)— and —(CH₂)_(o)NR⁵CONR⁷(CH₂)_(p)—, where o andp are independently integers from 0-6; wherein Y is selected from thegroup consisting of: —(CH₂)_(q)—, C₆₋₈aryl, a C₃₋₁₀cycloalkyl and

where q and r are independently integers of 0-4 and the sum of s and tis an integer of between 3 and 8; wherein Z is selected from the groupconsisting of —H, —COOH, —C(O)OR¹⁴ and —SO₂R¹⁴; wherein R⁵, R⁶, R⁷ andR¹³ are, for each structure they represent, independently selected fromthe group consisting of hydrogen, C₁₋₁₀alkyl, C₁₋₁₀alkenyl,C₁₋₁₀alkynyl, C₀₋₈alkylaryl, and C₃₋₁₀cycloalkyl; wherein R⁸, R⁹, R¹⁰,and R¹¹ are independently selected from the group consisting of H,alkyl, alkenyl, alkynyl, NHR⁵SO₂C₆₋₁₀aryl, C₆₋₁₀aryl,C₁₋₆alkyl-C₆₋₁₀aryl, a 5-10 member heterocycle, an amine linked 5-10membered heterocycle, and a 5-10 member heterocycle linked by aC₁₋₆alkyl, wherein said heterocycle is in each case selected from thegroup consisting of pyridine, pyrimidine, piperazine, pyrrole, furan,imidazole, oxazole, pyrazole, pyrroline, piperidine, morpholine,thiomorpholine, thiophene and pyrrolidine; wherein R¹² and R¹⁴ areindependently selected from the group consisting of —C₁₋₁₀alkyl,—C₃₋₁₀cycloalkyl, a —C₀₋₈alkyl-C₆₋₁₀aryl, and a 5-10 member heterocycleoptionally linked by a C₁₋₁₀alkyl or an amine, wherein said heterocycleis in each case selected from the group consisting of pyridine,pyrimidine, piperazine, pyrrole, furan, imidazole, oxazole, pyrazole,pyrroline, piperidine, morpholine, thiomorpholine, thiophene andpyrrolidine.
 27. A compound of claim 26, wherein X is selected from thegroup consisting of —(CH₂)_(o)CONH— and —(CH₂)_(o)NR₅CONR₆(CH₂)_(p)—.28. The compound of claim 27, wherein o is an integer from 0-2.
 29. Thecompound of claim 27, wherein p is and integer from 0-2.
 30. Thecompound of claim 27, wherein o is
 0. 31. The compound of claim 27,wherein p is
 0. 32. A compound of claim 27, wherein R⁵ is hydrogen or aC₁₋₄alkyl.
 33. A compound of claim 27, wherein R⁵ is H.
 34. A compoundof formula (I) or formula (II):

or a pharmaceutically acceptable salt or solvate thereof; wherein one ofR1 and R2 is —J—K—L, and the other is H; wherein one of R3 and R4 is—X—Y—Z, and the other is H; wherein J is selected from the groupconsisting of: —(CH₂)_(m)—, —(CH₂)_(m)CR⁵≡CR⁷(CH₂)_(n)—,—(CH₂)_(m)CR⁵≡CR⁷(CH₂)_(n)—, —(CH₂)_(m)O(CH₂)_(n)—,—(CH₂)_(m)S(CH₂)_(n)—, —(CH₂)_(m)NR⁵(CH₂)_(n)—, —(CH₂)_(m)CO(CH₂)_(n)—,—(CH₂)_(m)CS(CH₂)_(n)—, —(CH₂)_(m)SO₂(CH₂)_(n)—, —(CH₂)_(m)SO(CH₂)_(n)—,—(CH₂)_(m)C(O)O(CH₂)_(n)—, —(CH₂)_(m)OC(O)(CH₂)_(n)—,—(CH₂)_(m)SO₂NR⁵(CH₂)_(n)—, —(CH₂)_(m)NR⁵SO₂(CH₂)_(n)—,—(CH₂)_(m)CONR⁵(CH₂)_(n)—, —(CH₂)_(m)NR⁵CO(CH₂)_(n)—,—(CH₂)_(m)NR⁵(CH₂)_(n)CONH—, —(CH₂)_(m)O(CH₂)_(n)—CON H—,—(CH₂)_(m)NH(CH₂)_(n)SCSNR⁵—, —(CH₂)_(m)NH(CH₂)_(n)SCNHNH₂—, and anamine linked pyridine or pyrimidine, where m and n are independentlyintegers from 0-6; wherein K is selected from the group consisting of:—C₁₋₈alkyl—, —C₃₋₁₅cycloalkyl—, —C₆₋₁₅aryl—, —C₆₋₁₅aryl-C₁₋8alkyl—,—C₁₋₈alkyl-C₆₋₁₅aryl—, —C₁₋₈alkenyl—, —C₁₋₈alkynyl—, —(CH₂)_(q)NR⁶—,—CONR⁶—, —NHC(O)OCH₂—C₆₋₈aryl—, —CNHNH₂—, a pyrimidine, a pyridine, andan amine linked pyridine or pyrimidine; wherein L is selected from thegroup consisting of —H, —C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl, a pyrimidine,—C₆₋₁₀aryl, —C₁₋₁₀alkyl-C₆₋₁₀aryl, —NHR¹², —NR¹³C(N)NHR¹², —C(N)NHR¹²,—C(O)NHR¹², —NR¹³C(O)NHR, —SC(N)NHR¹², —SC(S)NHR¹², —OC(N)NHR¹²,—OC(O)NHR¹², and —C(O)OR²; wherein X is selected from the groupconsisting of: —(CH₂)_(o)—, —(CH₂)_(o)CR⁵≡CR⁷(CH₂)_(p)—,—(CH₂)_(o)CR⁵≡CR⁷(CH₂)_(p)—, —(CH₂)_(o)O(CH₂)_(p)—,—(CH₂)_(o)S(CH₂)_(p)—, —(CH₂)_(o)NR5(CH₂)_(p)—, —(CH₂)_(m)CO(CH₂)_(n)—,—(CH₂)_(m)CS(CH₂)_(n)—, —(CH₂)_(o)SO₂(CH₂)_(p)—, —(CH₂)_(o)SO(CH₂)_(p)—,—(CH₂)_(o)C(O)O(CH₂)_(p)—, —(CH₂)_(o)OC(O)(CH₂)_(p)—,—(CH₂)_(o)SO₂NR⁵(CH₂)_(p)—, —(CH₂)_(o)NR⁵SO₂(CH₂)_(p)—,—(CH₂)_(o)CONR⁵(CH₂)_(p)—, —(CH₂)_(o)NR⁵CO(CH₂)_(p)—,—(CH₂)_(o)NR⁵CONR⁷(CH₂)_(p)—, —(CH₂)_(o)NR⁵(CH₂)_(p)CONH—,—(CH₂)_(o)O(CH₂)_(p)CONH—, —(CH₂)_(o)NH(CH₂)_(p)SCSNR⁵—, and—(CH₂)_(o)NH(CH₂)_(p)SCNHNH₂—, where o and p are independently integersfrom 0-6; wherein Y is selected from the group consisting of:

where q and r are independently integers of 0-4 and the sum of s and tis an integer of between 3 and 8; wherein Z is selected from the groupconsisting of —H, —COOH, —C(O)OR¹⁴ and —SO₂R¹⁴; wherein R⁵, R⁶, R⁷ andR¹³ are, for each structure they represent, independently selected fromthe group consisting of hydrogen, C₁₋₁₀alkyl, C₁₋₁₀alkenyl,C₁₋₁₀alkynyl, C₀₋₈alkylaryl, and C₃₋₁₀cycloalkyl; wherein R⁸, R⁹, R¹⁰,and R¹¹ are independently selected from the group consisting of H,alkyl, alkenyl, alkynyl, NHR⁵SO₂C₆₋₁₀aryl, C₆₋₁₀aryl,C₁₋₆alkyl-C₆₋₁₀aryl, a 5-10 member heterocycle, an amine linked 5-10membered heterocycle, and a 5-10 member heterocycle linked by aC₁₋₆alkyl, wherein said heterocycle is in each case selected from thegroup consisting of pyridine, pyrimidine, piperazine, pyrrole, furan,imidazole, oxazole, pyrazole, pyrroline, piperidine, morpholine,thiomorpholine, thiophene and pyrrolidine; wherein R¹² and R¹⁴ areindependently selected from the group consisting of —C₁₋₁₀alkyl,—C₃₋₁₀cycloalkyl, a —C₀₋₈alkyl-C₆₋₁₀aryl, and a 5-10 member heterocycleoptionally linked by a C₁₋₁₀alkyl or an amine, wherein said heterocycleis in each case selected from the group consisting of pyridine,pyrimidine, piperazine, pyrrole, furan, imidazole, oxazole, pyrazole,pyrroline, piperidine, morpholine, thiomorpholine, thiophene andpyrrolidine.
 35. The compound of claim 34, wherein q is an integer of0-2.
 36. The compound of claim 34, wherein q is
 0. 37. The compound ofclaim 34, wherein is an integer of 0-2.
 38. The compound of claim 34,wherein r is
 0. 39. The compound of claim 34, wherein the sum of s and tis an integer of between 3 and
 5. 40. The compound of claim 34, whereinthe sum of s and r is
 4. 41. A compound of formula (I) or formula (II):

or a pharmaceutically acceptable salt or solvate thereof; wherein one ofR1 and R2 is —J—K—L, and the other is H; wherein one of R3 and R4 is—X—Y—Z, and the other is H; wherein J is selected from the groupconsisting of: —(CH₂)_(m)—, —(CH₂)_(m)CR⁵≡CR⁷(CH₂)_(n)—,—(CH₂)_(m)CR⁵≡CR⁷(CH₂)_(n)—, —(CH₂)_(m)O(CH₂)_(n)—,—(CH₂)_(m)S(CH₂)_(n)—, —(CH₂)_(m)NR⁵(CH₂)_(n)—, —(CH₂)_(m)CO(CH₂)_(n)—,—(CH₂)_(m)CS(CH₂)_(n)—, —(CH₂)_(m)SO₂(CH₂)_(n)—, —(CH₂)_(m)SO(CH₂)_(n)—,—(CH₂)_(m)C(O)O(CH₂)_(n)—, —(CH₂)_(m)OC(O)(CH₂)_(n)—,—(CH₂)_(m)SO₂NR⁵(CH₂)_(n)—, —(CH₂)_(m)NR⁵ SO₂(CH₂)_(n)—,—(CH₂)_(m)CONR⁵(CH₂)_(n)—, —(CH₂)_(m)NR⁵CO(CH₂)_(n)—,—(CH₂)_(m)NR⁵(CH₂)_(n)CONH—, —(CH₂)_(m)O(CH₂)_(n)CONH—,—(CH₂)_(m)NH(CH₂)_(n)SCSNR⁵—, —(CH₂)_(m)NH(CH₂)_(n)SCNHNH₂—, and anamine linked pyridine or pyrimidine, where m and n are independentlyintegers from 0-6; wherein K is selected from the group consisting of:—C₁₋₈alkyl—, —C₃₋₁₅cycloalkyl—, —C₆₋₁₅aryl—, —C₆₋₁₅aryl-C₁₋₈alkyl—,—C₁₋₈alkyl-C₆₋₁₅aryl—, —C₁₋₈alkenyl—, —C₁₋₈alkynyl—, —(CH₂)_(q)NR⁶—,—CONR⁶—, —NHC(O)OCH₂—C₆₋₈aryl—, —CNHNH₂—, a pyrimidine, a pyridine, andan amine linked pyridine or pyrimidine; wherein L is selected from thegroup consisting of: —H, —C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl, a pyrimidine,—C₆₋₁₀aryl, —C₁₋₁₀alkyl-C₆₋₁₀aryl, —NHR¹², —NR¹³C(N)NHR¹², —C(N)NHR¹²,—C(O)NHR¹², —NR¹³C(O)NHR¹², —SC(N)NHR¹², —SC(S)NHR¹², —OC(N)NHR¹²,—OC(O)NHR¹², and —C(O)OR¹²; wherein X is selected from the groupconsisting of: —(CH₂)_(o)—, —(CH₂)_(o)CR⁵≡CR⁷(CH₂)_(p)—,—(CH₂)_(o)CR⁵≡CR⁷(CH₂)_(p)—, —(CH₂)_(o)O(CH₂)_(p)—,—(CH₂)_(o)S(CH₂)_(p)—, —(CH₂)_(o)NR⁵(CH₂)_(p)—, —(CH₂)_(m)CO(CH₂)_(n)—,—(CH₂)_(m)CS(CH₂)_(n)—, —(CH₂)_(o)SO₂(CH₂)_(p)—, —(CH₂)_(o)SO(CH₂)_(p)—,—(CH₂)_(o)C(O)O(CH₂)_(p)—, —(CH₂)_(o)OC(O)(CH₂)_(p)—,—(CH₂)_(o)SO₂NR⁵(CH₂)_(p)—, —(CH₂)_(o)NR⁵SO₂(CH₂)_(p)—,—(CH₂)_(o)CONR⁵(CH₂)_(p)—, —(CH₂)_(o)NR⁵CO(CH₂)_(p)—,—(CH₂)_(o)NR⁵CONR⁷(CH₂)_(p)—, —(CH₂)_(o)NR⁵(CH₂)_(p)CONH—,—(CH₂)_(o)O(CH₂)_(p)CONH—, —(CH₂)_(o)NH(CH₂)_(p)SCSNR⁵—, and—(CH₂)_(o)NH(CH₂)_(p)SCNHNH₂—, where o and p are independently integersfrom 0-6; wherein Y is selected from the group consisting of:

where q and r are independently integers of 0-1 and the sum of s and tis an integer of between 3 and 8; wherein Z is selected from the groupconsisting of —H, —COOH, —C(O)OR¹⁴ and —SO₂R¹⁴; wherein R⁵, R⁶, R⁷ andR¹³ are, for each structure they represent, independently selected fromthe group consisting of hydrogen, C₁₋₁₀alkyl, C₁₋₁₀alkenyl,C₁₋₁₀alkynyl, C₀₋₈alkylaryl, and C₃₋₁₀cycloalkyl; wherein R⁸, R⁹, R¹⁰,and R¹¹ are independently selected from the group consisting of H,NHR⁵SO₂C₆₋₁₀aryl, C₅₋₁₀aryl, C₁₋₆alkyl-C₆₋₁₀aryl, NR⁵C₆₋₁₀aryl, apyrimidine, a pyrimidine linked by a C₁₋₆alkyl and an amine linkedpyrimidine; wherein R¹² and R¹⁴ are independently selected from thegroup consisting of —C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl, a—C₀₋₈alkyl-C₆₋₁₀aryl, and a 5-10 member heterocycle optionally linked bya C₁₋₁₀alkyl or an amine, wherein said heterocycle is selected from thegroup consisting of pyridine, pyrimidine, piperazine, pyrrole, furan,imidazole, oxazole, pyrazole, pyrroline, piperidine, morpholine,thiomorpholine, thiophene and pyrrolidine.
 42. The compound of claim 30,wherein one of R⁸ and R⁹ is not H and the other is H, and R¹⁰ and R¹¹are both H.
 43. A compound of claim 31, wherein said one of R⁸ and R⁹ isselected from the group consisting of: NHR⁵SO₂C₆aryl, C₆aryl,C₁₋₂alkyl-C₆aryl, a 6 member heterocycle, a 6 member heterocycle linkedby a C₁₋₂alkyl, and an amine linked 6 member, wherein said heterocycleis in each case selected from the group consisting of pyridine,pyrimidine, piperazine, piperidine, morpholine, and thiomorpholine. 44.A compound of claim 31, wherein said on of R₈ and R₉ is either a sixmember heterocycle, wherein said heterocycle is selected from the groupconsisting of pyridine, pyrimidine, piperazine, piperidine, morpholine,and thiomorpholine, or a phenyl substituted alternatively with one tothree substituents selected from the group comprising C₁₋₄alkyl,flourine, chlorine, bromine, and iodine.
 45. A compound of claim 31,wherein one of said R⁸ and R⁹ is a heterocycle optionally linked by aC₁₋₂alkyl or an amine, wherein said heterocycle is selected from thegroup consisting of pyridine, pyrimidine, piperazine, pyrrole, furan,imidazole, oxazole, pyrazole, pyrroline, piperidine, morpholinethiophene thiomorpholene and pyrrolidine.
 46. A compound of claim 1,wherein Z is selected from the group consisting of —H, —COOH, and—C(O)OR¹⁴.
 47. A compound of claim 1, wherein Z is selected from thegroup consisting of —H and —COOH.
 48. A pharmaceutical compositioncomprising the compound of claim 1 and a pharmaceutically acceptableexcipient.
 49. A method of inhibiting an integrin in a patient in needthereof comprising administering to said patient an integrin inhibitingeffective amount of a compound of formula (I) or formula (II):

or a pharmaceutically acceptable salt or solvate thereof; wherein one ofR1 and R2 is —J—K—L, and the other is H; wherein one of R3 and R4 is—X—Y—Z, and the other is H; wherein J is selected from the groupconsisting of: —(CH₂)_(m)—, —(CH₂)_(m)CR⁵≡CR⁷(CH₂)_(n)—,—(CH₂)_(m)CR⁵≡CR⁷(CH₂)_(n)—, —(CH₂)_(m)O(CH₂)_(n)—,—(CH₂)_(m)S(CH₂)_(n)—, —(CH₂)_(m)NR⁵(CH₂)_(n)—, —(CH₂)_(m)CO(CH₂)_(n)—,—(CH₂)_(m)CS(CH₂)_(n)—, —(CH₂)_(m)SO₂(CH₂)_(n)—, —(CH₂)_(m)SO(CH₂)_(n)—,—(CH₂)_(m)C(O)O(CH₂)_(n)—, —(CH₂)_(m)OC(O)(CH₂)_(n)—,—(CH₂)_(m)SO₂NR⁵(CH₂)_(n)—, —(CH₂)_(m)NR⁵SO₂(CH₂)_(n)—,—(CH₂)_(m)CONR⁵(CH₂)_(n)—, —(CH₂)_(m)NR⁵CO(CH₂)_(n)—,—(CH₂)_(m)NR⁵(CH₂)_(n)CONH—, —(CH₂)_(m)O(CH₂)_(n)CONH—,—(CH₂)_(m)NH(CH₂)_(n)SCSNR⁵—, —(CH₂)_(m)NH(CH₂)_(n)SCNHNH₂—, and anamine linked pyridine or pyrimidine, where m and n are independentlyintegers from 0-6; wherein K is selected from the group consisting of:—C₁₋₈alkyl—, —C₃₋₁₅cycloalkyl—, —C₆₋₁₅aryl—, —C₆₋₅aryl-C₁₋₈alkyl—,—C₁₋₈alkyl-C₆₋₁₅aryl—, —C₁₋₈alkenyl—, —C₁₋₈alkynyl—, —(CH₂)_(q)NR⁶—,—CONR⁶—, —NHC(O)OCH₂—C₆₋₈aryl—, —CNHNH₂—, a pyrimidine, a pyridine, andan amine linked pyridine or pyrimidine; wherein L is selected from thegroup consisting of: —H, —C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl, a pyrimidine,—C₆₋₁₀aryl, —C₁₋₁₀alkyl-C₆₋₁₀aryl, —NHR¹², —NR¹³C(N)NHR¹², —C(N)NHR¹²,—C(O)NHR¹², —NR¹³C(O)NHR¹², —SC()NHR¹², —SC(S)NHR¹², —OC(N)NHR¹²,—OC(O)NHR¹², and —C(O)OR¹²; wherein X is selected from the groupconsisting of: —(CH₂)_(o)—, —(CH₂)_(o)CR⁵≡CR⁷(CH₂)_(p)—,—(CH₂)_(o)CR⁵≡CR⁷(CH₂)_(p)—, —(CH₂)_(o)O(CH₂)_(p)—,—(CH₂)_(o)S(CH₂)_(p)—, —(CH₂)_(o)NR⁵(CH₂)_(p)—, —(CH₂)_(m)CO(CH₂)_(n)—,—(CH₂)_(m)CS(CH₂)_(n)—, —(CH₂)_(o)SO₂(CH₂)_(p)—, —(CH₂)_(o)SO(CH₂)_(p)—,—(CH₂)_(o)C(O)O(CH₂)_(p)—, —(CH₂)_(o)OC(O)(CH₂)_(p)—,—(CH₂)_(o)SO₂NR⁵(CH₂)_(p)—, —(CH₂)_(o)NR⁵SO₂(CH₂)_(p)—,—(CH₂)_(o)CONR⁵(CH₂)_(p)—, —(CH₂)_(o)NR⁵CO(CH₂)_(p)—,—(CH₂)_(o)NR⁵CONR⁷(CH₂)_(p)—, —(CH₂)_(o)NR⁵(CH₂)_(p)CONH—,—(CH₂)_(o)O(CH₂)_(p)CONH—, —(CH₂)_(o)NH(CH₂)_(p)SCSNR⁵—, and—(CH₂)_(o)NH(CH₂)_(p)SCNHNH₂—, where o and p are independently integersfrom 0-6; wherein Y is selected from the group consisting of:—(CH₂)_(q)—, C₆₋₈aryl, a C₃₋₁₀cycloalkyl and

where q and r are independently integers of 0-4 and the sum of s and tis an integer of between 3 and 8; wherein Z is selected from the groupconsisting of —H, —COOH, —C(O)OR¹⁴ and —SO₂R¹⁴; wherein R⁵, R⁶, R⁷ andR¹³ are, for each structure they represent, independently selected fromthe group consisting of hydrogen, C₁₋₁₀alkyl, C₁₋₁₀alkenyl,C₁₋₁₀alkynyl, C₀₋₈alkylaryl, and C₃₋₁₀cycloalkyl; wherein R⁸, R⁹, R¹⁰,and R¹¹ are independently selected from the group consisting of H,alkyl, alkenyl, alkynyl, NHR⁵SO₂C₆₋₁₀aryl, C₆₋₁₀aryl,C₁₋₆alkyl-C₆₋₁₀aryl, a 5-10 member heterocycle, an amine linked 5-10membered heterocycle, and a 5-10 member heterocycle linked by aC₁₋₁₀alkyl, wherein said heterocycle is in each case selected from thegroup consisting of pyridine, pyrimidine, piperazine, pyrrole, furan,imidazole, oxazole, pyrazole, pyrroline, piperidine, morpholine,thiomorpholine, thiophene and pyrrolidine; wherein R¹² and R¹⁴ areindependently selected from the group consisting of —C₁₋₁₀alkyl,—C₃₋₁₀cycloalkyl, a —C₀₋₈alkyl-C₆₋₁₀aryl, and a 5-10 member heterocycleoptionally linked by a C₁₋₁₀alkyl or an amine, wherein said heterocycleis in each case selected from the group consisting of pyridine,pyrimidine, piperazine, pyrrole, furan, imidazole, oxazole, pyrazole,pyrroline, piperidine, morpholine; thiomorpholine, thiophene andpyrrolidine.
 50. A method of inhibiting angiogenesis orneovascularization in a patient in need thereof comprising administeringto said patient an angiogenesis or neovascularization inhibitingeffective amount of a compound of formula (I) or formula (II):

or a pharmaceutically acceptable salt or solvate thereof; wherein one ofR1 and R2 is —J—K—L, and the other is H; wherein one of R3 and R4 is—X—Y—Z, and the other is H; wherein J is selected from the groupconsisting of: —(CH₂)_(m)—, —(CH₂)_(m)CR⁵≡CR⁷(CH₂)_(n)—,—(CH₂)_(m)CR⁵≡CR⁷(CH₂)_(n)—, —(CH₂)_(m)O(CH₂)_(n)—,—(CH₂)_(m)S(CH₂)_(n)—, —(CH₂)_(m)NR⁵(CH₂)_(n)—, —(CH₂)_(m)CO(CH₂)_(n)—,—(CH₂)_(m)CS(CH₂)_(n)—, —(CH₂)_(m)SO₂(CH₂)_(n)—, —(CH₂)_(m)SO(CH₂)_(n)—,—(CH₂)_(m)C(O)O(CH₂)_(n)—, —(CH₂)_(m)OC(O)(CH₂)_(n)—,—(CH₂)_(m)SO₂NR⁵(CH₂)_(n)—, —(CH₂)_(m)NR⁵SO₂(CH₂)_(n)—,—(CH₂)_(m)CONR⁵(CH₂)_(n)—, —(CH₂)_(m)NR⁵CO(CH₂)_(n)—,—(CH₂)_(m)NR⁵(CH₂)_(n)CONH—, —(CH₂)_(m)O(CH₂)_(n)CONH—,—(CH₂)_(m)NH(CH₂)_(n)SCSNR⁵—, —(CH₂)_(m)NH(CH₂)_(n)SCNHNH₂—, and anamine linked pyridine or pyrimidine, where m and n are independentlyintegers from 0-6; wherein K is selected from the group consisting of:—C₁₋₈alkyl—, —C₃₋₁₅cycloalkyl—, —C₃₋₁₅aryl—, —C₆₋₁₅aryl-C₁₋₈alkyl—,—C₁₋₈alkyl-C₆₋₁₅aryl—, —C₁₋₈alkenyl—, —C₁₋₈alkynyl—, —(CH₂)_(q)NR⁶—,—CONR⁶—, —NHC(O)OCH₂—C₆₋₈aryl—, —CNHNH₂—, a pyrimidine, a pyridine, andan amine linked pyridine or pyrimidine; wherein L is selected from thegroup consisting of: —H, —C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl, a pyrimidine,—C₆₋₁₀aryl, —C₁₋₁₀alkyl-C₆₋₁₀aryl —NHR¹², —NR³C(N)NHR¹², —C(N)NHR¹²,—C(O)NHR¹², —NR¹³C(O)NHR¹², —SC(N)NHR¹², —SC(S)NHR¹², —OC(N)NHR¹²,—OC(O)NHR¹², and —C(O)OR²; wherein X is selected from the groupconsisting of: —(CH₂)_(o)—, —(CH₂)_(o)CR⁵≡CR⁷(CH₂)_(p)—,—(CH₂)_(o)CR⁵≡CR⁷(CH₂)_(p)—, —(CH₂)_(o)O(CH₂)_(p)—,—(CH₂)_(o)S(CH₂)_(p)—, —(CH₂)_(o)NR⁵(CH₂)_(p)—, —(CH₂)_(m)CO(CH₂)_(n)—,—(CH₂)_(m)CS(CH₂)_(n)—, —(CH₂)_(o)SO₂(CH₂)_(p)—, —(CH₂)_(o)SO(CH₂)_(p)—,—(CH₂)_(o)C(O)O(CH₂)_(p)—, —(CH₂)_(o)OC(O)(CH₂)_(p)—,—(CH₂)_(o)SO₂NR⁵(CH₂)_(p)—, —(CH₂)_(o)NR⁵SO₂(CH₂)_(p)—,—(CH₂)_(o)CONR⁵(CH₂)_(p)—, —(CH₂)_(o)NR⁵CO(CH₂)_(p)—,—(CH₂)_(o)NR⁵CONR⁷(CH₂)_(p)—, —(CH₂)_(o)NR⁵(CH₂)_(p)CONH—,—(CH₂)_(o)O(CH₂)_(p)CONH—, —(CH₂)_(o)NH(CH₂)_(p)SCSNR⁵—, and—(CH₂)_(o)NH(CH₂)_(p)SCNHNH₂—, where o and p are independently integersfrom 0-6; wherein Y is selected from the group consisting of:—(CH₂)_(q)—, C₆₋₈aryl, a C₃₋₁₀cycloalkyl and where q and r areindependently integers of 0-4 and the sum of s and t is an integer ofbetween 3 and 8; wherein Z is selected from the group consisting of —H,—COOH, —C(O)OR¹⁴ and —SO₂R¹⁴; wherein R⁵, R⁶, R⁷ and R¹³ are, for eachstructure they represent, independently selected from the groupconsisting of hydrogen, C₁₋₁₀alkyl, C₁₋₁₀alkenyl, C₁₋₁₀alkynyl,C₀₋₈alkylaryl, and C₃₋₁₀cycloalkyl; wherein R⁸, R⁹, R¹⁰, and R¹¹ areindependently selected from the group consisting of H, alkyl, alkenyl,alkynyl, NHR⁵SO₂C₆₋₁₀aryl, C₆₋₁₀aryl, C₁₋₆alkyl-C₆₋₁₀aryl, a 5-10 memberheterocycle, an amine linked 5-10 membered heterocycle, and a 5-10member heterocycle linked by a C₁₋₆alkyl, wherein said heterocycle is ineach case selected from the group consisting of pyridine, pyrimidine,piperazine, pyrrole, furan, imidazole, oxazole, pyrazole, pyrroline,piperidine, morpholine, thiomorpholine, thiophene and pyrrolidine;wherein R¹² and R¹⁴ are independently selected from the group consistingof —C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl, a —C₀₋₈alkyl-C₆₋₁₀aryl, and a 5-10member heterocycle optionally linked by a C₁₋₁₀alkyl or an amine,wherein said heterocycle is in each case selected from the groupconsisting of pyridine, pyrimidine, piperazine, pyrrole, furan,imidazole, oxazole, pyrazole, pyrroline, piperidine, morpholine,thiomorpholine, thiophene and pyrrolidine.
 51. A method of treatingcancers that originate in the lung, breast, liver, kidney, brain,pancreas, ovary, uterus, testes, gastrointestinal tract, skin orprostrate in a patient in need thereof comprising administering to saidpatient an anticancer effective amount of a compound of formula (I) orformula (II):

or a pharmaceutically acceptable salt or solvate thereof; wherein one ofR1 and R2 is —J—K—L, and the other is H; wherein one of R3 and R4 is—X—Y—Z, and the other is H; wherein J is selected from the groupconsisting of: —(CH₂)_(m)—, —(CH₂)_(m)CR⁵≡CR⁷(CH₂)_(n)—,—(CH₂)_(m)CR⁵≡CR⁷(CH₂)_(n)—, —(CH₂)_(m)O(CH₂)_(n)—,—(CH₂)_(m)S(CH₂)_(n)—, —(CH₂)_(m)NR⁵(CH₂)_(n)—, —(CH₂)_(m)CO(CH₂)_(n)—,—(CH₂)_(m)CS(CH₂)_(n)—, —(CH₂)_(m)SO₂(CH₂)_(n)—, —(CH₂)_(m)SO(CH₂)_(n)—,—(CH₂)_(m)C(O)O(CH₂)_(n)—, —(CH₂)_(m)OC(O)(CH₂)_(n)—,—(CH₂)_(m)SO₂NR⁵(CH₂)_(n)—, —(CH₂)_(m)NR⁵SO₂(CH₂)_(n)—,—(CH₂)_(m)CONR⁵(CH₂)_(n)—, —(CH₂)_(m)NR⁵CO(CH₂)_(n)—,—(CH₂)_(m)NR⁵(CH₂)_(n)CONH—, —(CH₂)_(m)O(CH₂)_(n)CONH—,—(CH₂)_(m)NH(CH₂)_(n)SCSNR⁵—, —(CH₂)_(m)NH(CH₂)_(n)SCNHNH₂—, and anamine linked pyridine or pyrimidine, where m and n are independentlyintegers from 0-6; wherein K is selected from the group consisting of:—C₁₋₈alkyl—, —C₃₋₁₅cycloalkyl—, —C₆₋₁₅aryl—, —C₆₋₁₅aryl-C₁₋₈alkyl—,—C₁₋₈alkyl-C₆₋₁₅aryl—, —C₁₋₈alkenyl—, —C₁₋₈alkynyl—, —(CH₂)_(q)NR⁶—,—CONR⁶—, —NHC(O)OCH₂—C₆₋₈aryl—, —CNHNH₂—, a pyrimidine, a pyridine, andan amine linked pyridine or pyrimidine; wherein L is selected from thegroup consisting of: —H, —C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl, a pyrimidine,—C₆₋₁₀aryl, —C₁₋₁₀alkyl-C₆₋₁₀aryl, —NHR¹², —NR¹³C(N)NHR¹², —C(N)NHR¹²,—C(O)NHR¹², —NR¹³C(O)NHR¹², —SC(N)NHR¹², —SC(S)NHR¹², —OC(N)NHR¹²,—OC(O)NHR¹², and —C(O)OR¹²; wherein X is selected from the groupconsisting of: —(CH₂)_(o)—, —(CH₂)_(o)CR⁵≡CR⁷(CH₂)_(p)—,—(CH₂)_(o)CR⁵≡CR⁷(CH₂)_(p)—, —(CH₂)_(o)O(CH₂)_(p)—,—(CH₂)_(o)S(CH₂)_(p)—, —(CH₂)_(o)NR⁵(CH₂)_(p)—, —(CH₂)_(m)CO(CH₂)_(n)—,—(CH₂)_(m)CS(CH₂)_(n)—, —(CH₂)_(o)SO₂(CH₂)_(p)—, —(CH₂)_(o)SO(CH₂)_(p)—,—(CH₂)_(o)C(O)O(CH₂)_(p)—, —(CH₂)_(o)OC(O)(CH₂)_(p)—,—(CH₂)_(o)SO₂NR⁵(CH₂)_(p)—, —(CH₂)_(o)NR⁵SO₂(CH₂)_(p)—,—(CH₂)_(o)CONR⁵(CH₂)_(p)—, —(CH₂)_(o)NR⁵CO(CH₂)_(p)—,—(CH₂)_(o)NR⁵CONR⁷(CH₂)_(p)—, —(CH₂)_(o)NR⁵(CH₂)_(p)CONH—,—(CH₂)_(o)O(CH₂)_(p)CONH—, —(CH₂)_(o)NH(CH₂)_(p)SCSNR⁵—, and—(CH₂)_(o)NH(CH₂)_(p)SCNHNH₂—, where o and p are independently integersfrom 0-6; wherein Y is selected from the group consisting of:—(CH₂)_(q)—, C₆₋₈aryl, a C₃₋₁₀cycloalkyl and

where q and r are independently integers of 0-4 and the sum of s and tis an integer of between 3 and 8; wherein Z is selected from the groupconsisting of —H, —COOH, —C(O)OR¹⁴ and —SO₂R¹⁴; wherein R⁵, R⁶, R⁷ andR¹³ are, for each structure they represent, independently selected fromthe group consisting of hydrogen, C₁₋₁₀alkyl, C₁₋₁₀alkenyl,C₁₋₁₀alkynyl, C₀₋₈alkylaryl, and C₃₋₁₀cycloalkyl; wherein R⁸, R⁹, R¹⁰,and R₁₁ are independently selected from the group consisting of H,alkyl, alkenyl, alkynyl, NHR⁵SO₂C₆₋₁₀aryl, C₆₋₁₀aryl,C₁₋₆alkyl-C₆₋₁₀aryl, a 5-10 member heterocycle, an amine linked 5-10membered heterocycle, and a 5-10 member heterocycle linked by aC₁₋₆alkyl, wherein said heterocycle is in each case selected from thegroup consisting of pyridine, pyrimidine, piperazine, pyrrole, furan,imidazole, oxazole, pyrazole, pyrroline, piperidine, morpholine,thiomorpholine, thiophene and pyrrolidine; wherein R¹² and R¹⁴ areindependently selected from the group consisting of —C₁₋₁₀alkyl,—C₃₋₁₀cycloalkyl, a —C₀₋₈alkyl-C₆₋₁₀aryl, and a 5-10 member heterocycleoptionally linked by a C₁₋₁₀alkyl or an amine, wherein said heterocycleis in each case selected from the group consisting of pyridine,pyrimidine, piperazine, pyrrole, furan, imidazole, oxazole, pyrazole,pyrroline, piperidine, morpholine, thiomorpholine, thiophene andpyrrolidine.
 52. A compound of formula (I) or formula (II):

or a pharmaceutically acceptable salt or solvate thereof; wherein one ofR1 and R2 is —J—K—L, and the other is H; wherein one of R3 and R4 is—X—Y—Z, and the other is H; wherein J is selected from the groupconsisting of: —(CH₂)_(m)—, —(CH₂)_(m)O(CH₂)_(n)— and—(CH₂)_(m)NR⁵(CH₂)_(n); wherein K is selected from the group consistingof: —C₁₋₈alkyl—, a —C₃₋₁₅cycloalkyl—, and a pyrimidine; wherein L isselected from the group consisting of: a pyrimidine, C₆₋₁aryl, —NHR¹²,—NR¹³C(N)NHR¹², —C(N)NHR¹², —C(O)NHR¹², —NR¹³C(O)NHR¹², —SC(N)NHR¹²,—SC(S)NHR¹², and —OC(N)NHR¹²; wherein X is selected from the groupconsisting of: —(CH₂)_(o)CO NH— and —(CH₂)_(o)NR₅CONR₆(CH₂)_(p)—;wherein Y is selected from the group consisting of: —(CH₂)_(q)—, andwherein q, r, s, and t are independently integers of 0-4 and the sum ofs and t is an integer between 3 and 8; wherein Z is selected from thegroup consisting of —H and —COOH; wherein R⁵, R⁶, R⁷ and R¹³ are, foreach structure they represent, independently selected from the groupconsisting of hydrogen and C₁₋₄alkyl; wherein R⁸, R⁹, R¹⁰, and R¹¹ areindependently selected from the group consisting of H, NHR⁵SO₂C₆₋₁₀aryl,C₆₋₁₀aryl, C₁₋₆alkyl-C₆₋₁₀aryl, NR⁵C₅₋₁₀aryl, a 5-10 member heterocycle,an amine linked 5-10 membered heterocycle, and a 5-10 member heterocyclelinked by a C₁₋₆alkyl, wherein said heterocycle is in each case selectedfrom the group consisting of pyridine, pyrimidine, piperazine, pyrrole,furan, imidazole, oxazole, pyrazole, pyrroline, piperidine, morpholine,thiomorpholine, thiophene and pyrrolidine; and wherein R¹² is selectedfrom the group consisting of a —C₁₋₄alkyl, a —C₀₋₄alkyl-C₆₋₇aryl and a5-10 member heterocycle optionally linked by a C₁₋₁₀alkyl or an amine,wherein said heterocycle is in each case selected from the groupconsisting of pyridine, pyrimidine, piperazine, pyrrole, furan,imidazole, oxazole, pyrazole, pyrroline, piperidine,

morpholine, thiomorpholine, thiophene and pyrrolidine.
 53. The compoundof claim 52, of formula I.
 54. The compound or claim 52, of formula II.55. The compound of claim 52, wherein m is an integer between 0-1. 56.The compound of claim 52, wherein n is an integer between 0-1.
 57. Acompound of claim 52, wherein R⁵ and R⁷ is H or a C₁₋₄alkyl.
 58. Thecompound of claim 52, wherein K is a —C₁alkyl—.
 59. The compound ofclaim 52, wherein K is a —C₅₋₈cycloalkyl—.
 60. The compound of claim 52,wherein R¹³ is a C₁₋₅alkyl or H.
 61. A compound of claim 52, wherein R¹²is a optionally linked by a C₁₋₂alkyl or an amine.
 62. The compound ofclaim 52, wherein R¹² is a C₆aryl optionally linked by a C₁₋₂alkyl or anamine.
 63. The compound of claim 52, wherein o is an integer from 0-1.64. The compound of claim 52, wherein p is and integer from C-1.
 65. Thecompound of claim 52, wherein R⁵ and R⁷ are independently H or aC₁₋₄alkyl.
 66. The compound of claim 52, wherein q is an integer of 0-1.67. The compound of claim 52, wherein r is an integer of 0-1.
 68. Thecompound of claim 52, wherein the sum of s and t is
 4. 69. A compound ofclaim 52, wherein Y is

wherein q and r are independently integers of 0-1.
 70. The compound ofclaim 52, wherein one of R⁸ and R⁹ is nor H and the other is H, and R¹⁰and R¹¹ are both H.
 71. A compound of claim 52, wherein said one of R⁸and R⁹ is selected from the group consisting of: NHR⁵SO₂C₆aryl, C₆aryl,C₁₋₂alkyl-C₆aryl, a pyrimidine, a pyrimidine linked by a C₁₋₂alkyl, andan amine linked pyrimidine.
 72. A compound of claim 52, wherein said onof R₈ and R⁹ is either a pyrimidine or a phenyl substitutedalternatively with one to three substituents selected from the groupcomprising C₁₋₄alkyl, flourine, chlorine, bromine, or iodine.
 73. Acompound of claim 52, wherein one of said R⁸ and R⁹ is a heterocycleoptionally linked by a C₁₋₂alkyl or an amine, wherein said heterocycleis selected from the group consisting of pyridine, pyrimidine,piperazine, pyrrole, furan, imidazole, oxazole, pyrazole, pyrroline, andpyrrolidine.
 74. A compound of claim 52, wherein R3 is H and R4 is—J—K—L.
 75. The compound of claim 74, wherein J is selected from thegroup consisting of —(CH₂)_(m)— and —(CH₂)_(m)O(CH₂)_(n)—, wherein m andn are independently integers from 0-3; wherein K is a —C₁₋₈alkyl—;wherein L is selected from the group consisting of —NH₂,

wherein X is —(CH₂)_(o)CO NH—, wherein o is an integer from 0-3; whereinY is selected from the group consisting of:

wherein q, r, s, and t are independently integers of 0-4, and the sum ofs and t is 4; wherein R¹⁵, R¹⁶, and R¹⁷ are independently selected fromthe group consisting of —H, C₁₋₄alkyl and halogen (F, Cl, Br, and I);and wherein Z is —COOH.
 76. The compound of claim 52, wherein R³ is Hand R⁴ is X—Y—Z.
 77. The compound of claim 76, wherein J is defined as—(CH₂)_(m)O(CH₂)_(n)—, where m and n are independently integers from0-3; wherein K is a —C₁₋₈alkyl—; wherein L is selected from the groupconsisting of —NH₂,

wherein X is selected from the group consisting of: —(CH₂)_(o)CO NH— and—(CH₂)_(o)NR⁵CONR⁷ (CH₂)_(p)—, where o and p are independently integersfrom 0-3; wherein Y is selected from the group consisting of:

where q, r, s, and t are independently integers of 0-4, and wherein thesum of s and t is 4; wherein R¹⁵, R¹⁶, and R¹⁷ are independentlyselected from the group consisting of —H, C₁₋₄alkyl and halogen; andwherein Z is —COOH.
 78. A compound of claim 52, wherein R1 is —J—K—L andR2 is H.
 79. The compound of claim 78, wherein R3 is —X—Y—Z and R4 is H.80. The compound of claim 79, wherein J is —(CH₂)_(m)O(CH₂)_(n)—, wherem and n are independently integers from 0-3; wherein K is —C₁₋₈alkyl—;wherein L is selected from the group consisting of —NH₂ and

wherein X is —(CH₂)_(o)CO NH—, where o is an integer from 0-3; wherein Yis selected from the group consisting of:

wherein R¹⁵, R¹⁶, and R¹⁷ are independently selected from the groupconsisting of hydrogen, C₁₋₄alkyl and halogen; and wherein Z is —COOH.81. The compound of claim 52 wherein R1 is —J—K—L, R2 is H, R3 is H andR4 is —X—Y—Z.
 82. The compound of claim 81, wherein J is selected fromthe group consisting of: —N—, —N(CH₃)—, and an amine linked pyridine orpyrimidine wherein K is selected from the group consisting of:—C₁₋₈alkyl— and —C₃₋₁₅cycloalkyl—; wherein L is selected from the groupconsisting of —NH₂ and

wherein X is —(CH₂)_(o)CO NH—, where o is an integer from 0-3; wherein Yis selected from the group comprising:

wherein Z is —COOH; and wherein R¹⁵, R¹⁶, and R¹⁷ are independentlyselected from the group consisting of hydrogen, C₁₋₁₀alkyl and halogen.83. The compound of claim 52, wherein is selected from the groupconsisting of —NH₂ and


84. The compound of claim 52, wherein Y is selected from the groupconsisting of

wherein q, r, s, and t are independently integers of 0-4 and the sum ofs and t is an integer between 3 and 8; and wherein R¹⁵, R¹⁶, and R¹⁷ areindependently selected from the group consisting of —H, C₁₋₄alkyl andhalogen.
 85. A method of inhibiting angiogenesis in a patient comprisingadministering an angiogenesis inhibiting effective amount of a compoundof claim 1 to said patient.
 86. A quinolizine compound selected from:2-benzylsulfonylamino-3-{[7-(5-aminopentyloxy)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-propionicacid TFA salt;2-benzylsulfonylamino-3-{[7-(5-guanidinopentyloxy)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-propionicacid hydrochloride;2-benzylsulfonylamino-3-{[7-(3-aminopentyloxy)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-propionicacid TFA salt;2-benzylsulfonylamino-3-{[7-(5-guanidinopropyloxy)-4-oxo-4H-quinolizine-3-carbonyl]-amino}3-propionicacid hydrochloride;′(trans)-2-{[7′-(3″-amino-propoxy)-4′-oxo-4′H-quinolizine-3′-carbonyl]-amino}-cyclohexanecarboxylicacid trifluoroacetic acid salt;′7(r,s)-3-benzoyloxycarbonylaminopropyl)oxo-3-carboxy-3-phenylsulfonylamino-1-yl)aminocarbonylaminoethyl)quinolizin-4-one;′7(r,s)-3-((aminopropyl)oxo-3-carboxy-3-phenylsulphonylamino-1-yl)aminocarbonylaminoethyl)quinolizin-4-one;′7(r,s)-((3-guanidinoaminopropyl)oxy-3-carboxy-1-pyridyl1-ethyl)aminocarbonylamino)quinolizin-4-one;2-Benzenesulfonylamino-3-{3-[7-(3-guanidino-propoxy)-4-oxo-4H-quinolizin-3-yl]-ureido}-propionicacid trifluoroacetate;3-Phenyl-3-{[7-(3-benzyl-ureidopropoxy)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-propionicacid;3-{[7-(3-tert-Butoxycarbonylamino-propoxy)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-3-phenyl-propionicacid ethyl ester;(S)-2-Benzenesulfonylamino-3-({7-[3-(3-methyl-ureido)-propoxy]-4-oxo-4H-quinolizine-2-carbonyl}-amino)-propionicacid; 7-(3-amino-propyloxy)-4-oxo-4H-quinolizine-2-carboxylic acid TFAsalt;2-Benzenesulfonylamino-3-{[7-(3-amino-propoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino)}-propionicacid TFA salt;2-Benzenesulfonylamino-3-{[7-(3-guanidino-propoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionicacid hydrochloride;3-{[7-(3-amino-propoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionicacid TFA salt;2-Benzenesulfonylamino-3-{[7-(4-amino-butoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionicacid TFA salt;2-Benzenesulfonylamino-3-{[7-(4-guanidino-butoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionicacid hydrochloride.;2-Benzenesulfonylamino-3-{[7-(4-amino-ethoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionicacid;2-Benzenesulfonylamino-3-{[7-(4-guanidino-ethoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionicacid;3-{[7-(3-Amino-propoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-2-(pyrimidin-2-ylamino)-propionicacid hydrochloride;3-{[7-(3-Guanidino-propoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-2-(pyrimidin-2-ylamino)-propionicacid hydrochloride;3-{[7-(3-Amino-propoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-2-(benzenesulfonyl-methyl-amino)-propionicacid trifluoroacetate;2-(Benzenesulfonyl-methyl-amino)-3-{[7-(3-guanidino-propoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionicacid hydrochloride;′2-benzenesulfonylamino-3-({4-oxo-7-[3-(pyrimidin-2-ylamino)-propoxy]-4H-quinolizine-2-carbonyl}-amino)-propionicacid;3-[(7-Aminomethyl-4-oxo-4H-quinolizine-2-carbonyl)-amino]-2-benzenesulfonylamino-propionicacid;2-Benzenesulfonylamino-3-[(7-guanidinomethyl-4-oxo-4H-quinolizine-2-carbonyl)-amino]-propionicacid;3-[(7-Aminomethyl-4-oxo-6,7,8,9-tetrahydro-4H-quinolizine-2-carbonyl)-amino]-2-benzenesulfonylamino-propionicacid;2-Benzenesulfonylamino-3-[(7-guanidinomethyl-4-oxo-6,7,8,9-tetrahydro-4H-quinolizine-2-carbonyl)-amino]-propionicacid;3-{[8-(3-Amino-propoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-2-benzenesulfonylamino-propionicacid trifluoroacetate;2-Benzenesulfonylamino-3-{[8-(3-guanidino-propoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionicacid hydrochloride;3-{[8-(4-Amino-butoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-2-benzenesulfonylamino-propionicacid trifluoroacetate;2-Benzenesulfonylamino-3-{[8-(4-guanidino-butoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionicacid hydrochloride;3-{[8-(5-Amino-pentyloxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-2-benzenesulfonylamino-propionicacid trifluoroacetate;2-Benzenesulfonylamino-3-{[8-(5-guanidino-pentyloxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionicacid hydrochloride;3-{[8-(2-amino-ethylamino)-4-oxo-4H-quinolizine-3-carbonyl]-aminosymbol125 \f “Symbol”\s 12-3-phenyl-propionic acid;3-{[8-(2-Carbamimidoylsulfanyl-ethylamino)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-3-phenyl-propionicacid trifluoroacetate;3-({4-Oxo-8-[2-(pyridin-3-ylthiocarbamoylsulfanyl)-ethylamino]-4H-quinolizine-3-carbonyl}-amino)-3-phenyl-propionicacid trifluoroacetate;3-[(8-{Methyl-[2-(N-methyl-guanidino)-ethyl]-amino}-4-oxo-4H-quinolizine-3-carbonyl)-amino]-3-phenyl-propionicacid trifluoroacetate;3-{[8-(4-Carbamimidoyl-piperazin-1-yl)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-3-phenyl-propionicacid trifluoroacetate;3-{[8-(4-Guanidino-cyclohexylamino)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-3-phenyl-propionicacid trifluoroacetate;(+/−)-3-(3,5-Dichlorophenyl)-3-[(7-guanidinomethyl-4-oxo-4H-quinolizine-2-carbonyl)-amino]-propionicacid trifluoroacetic acid salt;(+/−)-3-[(7-guanidinomethyl-4-oxo-4H-quinolizine-2-carbonyl)-amino]-3-pyridin-3-yl-propionicacid bis-trifluoroacetic acid salt;(+/−)-3-[(7-guanidinomethyl-4-oxo-4H-quinolizine-2-carbonyl)-amino]-2-(pyrimidin-2-ylamino)-propionicacid bis-trifluoroacetic acid salt;(S)-2-Benzenesulfonylamino-3-{[(7-benzyloxycarbonylamino-methyl)-4-oxo-4H-quinolizine-2-carbonyl]-aminosymbol125 \f “Kino MT”\s 12-propionic acid;(S)-2-Benzenesulfonylamino-3-{[4-oxo-7-(pyrimidin-2-ylamninomethyl)-4H-quinolizine-2-carbonyl]-aminosymbol125 \f “Kino MT”\s 12-propionic acid trifluoroacetic acid salt;(S)-2-Benzenesulfonylamino-3-{[7-(3-benzyl-ureidomethyl)-4-oxo-4H-quinolizine-2-carbonyl]-aminosymbol125 \f “Kino MT”\s 12-propionic acid;(S)-2-Benzyloxycarbonylamino-3-[(7-guanidinomethyl-4-oxo-4H-quinolizine-2-carbonyl)-amino]-propionicacid trifluoroacetic acid salt; and(S)-3-[(7-guanidinomethyl-4-oxo-4H-quinolizine-2-carbonyl)-amino]-2-(2,4,6-trimethyl-benzenesulfonylamino)-propionicacid hydrochloride.
 87. A compound of formula (I) or formula (II):

or a pharmaceutically acceptable salt or solvate thereof; wherein one ofR1 and R2 is —J—K—L, and the other is H; wherein one of R3 and R4 is—X—Y—Z, and the other is H; wherein J is selected from the groupconsisting of: —(CH₂)_(m)—, —(CH₂)_(m)CR⁵≡CR⁷(CH₂)_(n)—,—(CH₂)_(m)CR⁵≡CR⁷(CH₂)_(n)—, —(CH₂)_(m)O(CH₂)_(n)—,—(CH₂)_(m)S(CH₂)_(n)—, —(CH₂)_(m)NR⁵(CH₂)_(n)—, —(CH₂)_(m)CO(CH₂)_(n)—,—(CH₂)_(m)CS(CH₂)_(n)—, —(CH₂)_(m)SO₂(CH₂)_(n)—, —(CH₂)_(m)SO(CH₂)_(n)—,—(CH₂)_(m)C(O)O(CH₂)_(n)—, —(CH₂)_(m)OC(O)(CH₂)_(n)—,—(CH₂)_(m)SO₂NR⁵(CH₂)_(n)—, —(CH₂)_(m)NR⁵SO₂(CH₂)_(n)—,—(CH₂)_(m)CONR⁵(CH₂)_(n)—, —(CH₂)_(m)NR⁵CO(CH₂)_(n)—,—(CH₂)_(m)NR⁵(CH₂)_(n)CONH—, —(CH₂)_(m)O(CH₂)_(n)CONH—,—(CH₂)_(m)NH(CH₂)_(n)SCSNR⁵—, —(CH₂)_(m)NH(CH₂)_(n)SCNHNH₂—, and anamine linked pyridine or pyrimidine, where m and n are independentlyintegers from 0-6; wherein K is selected from the group consisting of:—C₁₋₈alkyl—, —C₃₋₁₅cycloalkyl—, —C₆₋₁₅aryl—, —C₆₋₁₅aryl-C₁₋₈alkyl—,—C₁₋₈alkyl-C₆₋₁₅aryl—, —C₁₋₈alkenyl—, —C₁₋₈alkynyl—, —(CH₂)_(q)NR⁶—,—CONR⁶—, —NHC(O)OCH₂—C₆₋₈aryl—, —CNHNH₂—, a pyrimidine, a pyridine, andan amine linked pyridine or pyrimidine; wherein L is selected from thegroup consisting of: a pyrimidine, —NHR¹², —NR³C(N)NHR¹², —C(N)NHR¹²,—C(O)NHR¹², —NR¹³C(O)NHR¹², —SC(N)NHR¹², —SC(S)NHR¹², —OC(N)NHR¹²,—OC(O)NHR¹², and —C(O)OR¹²; wherein X is —(CH₂)_(o)CONH— or—(CH₂)_(o)NR⁵CONR⁷(CH₂)_(p), where o and p are both 0-6; wherein Y isselected from the group consisting of: —(CH₂)_(q)—, C₆₋₈aryl, aC₃₋₁₀cycloalkyl and

where q and r are independently integers of 0-4and the sum of s and t isan integer of between 3 and 8; wherein Z is selected from the groupconsisting of —H, —COOH, —C(O)OR¹⁴ and —SO₂R¹⁴; wherein R⁵, R⁶, R⁷ andR¹³ are, for each structure they represent, independently selected fromthe group consisting of hydrogen, C₁₋₁₀alkyl, C₁₋₁₀alkenyl,C₁₋₁₀alkynyl, C₀₋₈alkylaryl, and C₃₋₁₀cycloalkyl; wherein R⁸, R⁹, R¹⁰,and R¹¹ are independently selected from the group consisting of H,alkyl, alkenyl, alkynyl, NHR⁵SO₂C₆₋₁₀aryl, C₆₋₁₀aryl,C₁₋₆alkyl-C₆₋₁₀aryl, a 5-10 member heterocycle, an amine linked5-10membered heterocycle, and a 5-10 member heterocycle linked by aC₁₋₆alkyl, wherein said heterocycle is in each case selected from thegroup consisting of pyridine, pyrimidine, piperazine, pyrrole, furan,imidazole, oxazole, pyrazole, pyrroline, piperidine, morpholine,thiomorpholine, thiophene and pyrrolidine; wherein R¹² and R¹⁴ areindependently selected from the group consisting of —C₁₋₁₀alkyl,—C₃₋₁₀cycloalkyl, a —C₀₋₈alkyl-C₆₋₁₀aryl, and a 5-10member heterocycleoptionally linked by a C₁₋₁₀alkyl or an amine, wherein said heterocycleis in each case selected from the group consisting of pyridine,pyrimidine, piperazine, pyrrole, furan, imidazole, oxazole, pyrazole,pyrroline, piperidine, morpholine; thiomorpholine, thiophene andpyrrolidine.